5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines

ABSTRACT

This invention is directed to dihydropyrimidine compounds of the following formula:                    
     which are selective antagonists for human α 1C  receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotence, cardiac arrhythmia and for the treatment of any disease where antagonism of the α 1C  receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

This application is the National Stage Application of PCT InternationalApplication No. PCT/US95/15025, filed Nov. 16, 1994, which is acontinuation-in-part of U.S. Ser. No. 08/340,611, filed Nov. 16, 1994,now abandoned, the contents of which are incorporated by reference.Disclosures of these publications in their entireties are herebyincorporated by reference into this application to more fully describethe state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

The designation “α_(1A)” is the appellation recently approved by theIUPHAR Nomenclature Committee for the previously designated “α_(1C)”cloned subtype as outlined in the 1995 Receptor and Ion ChannelNomenclature Supplement (Watson and Girdlestone, 1995). However, thedesignation α_(1C) is used throughout this application and thesupporting tables and figures to refer to the receptor subtype recentlyrenamed “α_(1A)”. Since in both the old and new nomenclature there hasonly been one unique receptor subtype which has been designated α_(1C)(i.e., there is no α_(1C) under the current nomenclature), “α_(1C)” isan unambiguous description of this unique receptor subtype.

Benign Prostatic Hyperplasia (BPH), also called Benign ProstaticHypertrophy, is a progressive condition which is characterized by anodular enlargement of prostatic tissue resulting in obstruction of theurethra. This results in increased frequency of urination, nocturia, apoor urine stream and hesitancy or delay in starting the urine flow.Chronic consequences of BPH can include hypertrophy of bladder smoothmuscle, a decompensated bladder and an increased incidence of urinarytract infection. The specific biochemical, histological andpharmacological properties of the prostate adenoma leading to thebladder outlet obstruction are not yet known. However, the developmentof BPH is considered to be an inescapable phenomenon for the aging malepopulation. BPH is observed in approximately 70% of males over the ageof 70. Currently, in the United States, the method of choice fortreating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17, 651(1990)). Over 400,000 prostatectomies are performed annually (data from1986). A medicinal alternative to surgery is clearly very desirable. Thelimitations of surgery for treating BPH include the morbidity rate of anoperative procedure in elderly men, persistence or recurrence ofobstructive and irritative symptoms, as well as the significant cost ofsurgery.

α-Adrenergic receptors (McGrath, et. al. Med. Res. Rev., 9, 407-533,1989) are specific neuroreceptor proteins located in the peripheral andcentral nervous systems on tissues and organs throughout the body. Thesereceptors are important switches for controlling many physiologicalfunctions and, thus, represent important targets for drug development.In fact, many α-adrenergic drugs have been developed over the past 40years. Examples include clonidine, phenoxybenzamine and prazosin(treatment of hypertension), naphazoline (nasal decongestant), andapraclonidine (treating glaucoma). α-Adrenergic drugs can be broken downinto two distinct classes: agonists (clonidine and naphazoline areagonists), which mimic the receptor activation properties of theendogenous neurotransmitter norepinephrine, and antagonists(phenoxybenzamine and prazosin are antagonists), which act to block theeffects of norepinephrine. Many of these drugs are effective but alsoproduce unwanted side effects (for example, clonidine produces dry mouthand sedation in addition to its antihypertensive effects).

During the past 15 years a more precise understanding of α-adrenergicreceptors and their drugs has evolved through increased scientificscrutiny. Prior to 1977, only one α-adrenergic receptor was known toexist. Between 1977 and 1988, it was accepted by the scientificcommunity that at least two α-adrenergic receptors—α₁ and α₂—existed inthe central and peripheral nervous systems. Since 1988, new techniquesin molecular biology have led to the identification of at least sixα-adrenergic receptors which exist throughout the central and peripheralnervous systems: α_(1A), α_(1B), α_(1C), α^(2A), α_(2B) and α_(2C)(Bylund, D. B., FASEB J., 6, 832 (1992)). In many cases, it is not knownprecisely which physiological responses in the body are controlled byeach of these receptors. In addition, current α-adrenergic drugs are notselective for any particular α-adrenergic receptor. Many of these drugsproduce untoward side effects which may be attributed to their poorα-adrenergic receptor selectivity.

Since the mid 1970's, nonselective α-antagonists have been prescribed totreat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)),reported that the nonselective α-antagonist phenoxybenzamine was usefulin relieving the symptoms of BPH. This drug may produce its effects byinteracting with α-receptors located on the prostate. However, this drugalso produces significant side effects such as dizziness and astheniawhich severely limit its use in treating patients on a chronic basis.More recently, the α-adrenergic antagonists prazosin and terazosin havealso been found to be useful for treating BPH. However, these drugs alsoproduce untoward side effects. It has recently been discovered that theα_(1C) receptor is responsible for mediating the contraction of humanprostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994;Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994). This discoveryindicates that the α_(1C) antagonists may be effective agents for thetreatment of BPH with decreased side effects. Further studies haveindicated that the aic receptor may also be present in other lowerurinary tract tissues, such as urethral smooth muscle (Ford et al. Br.J. Pharmacol., 114, 24P, (1995)).

This invention is directed to dihydropyrimidine compounds which areselective antagonists for cloned human α_(1C) receptors. This inventionis also related to uses of these compounds for lowering intraocularpressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928,1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J.Cardiovascular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatichyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991),sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiacarrhythmia (Spiers, et. al., J. Cardiovascular Pharmacol., 16, 824-830,1990) and for the treatment of any disease where antagonism of theα_(1C) receptor may be useful.

SUMMARY OF THE INVENTION

This invention is directed to dihydropyrimidine compounds which areselective antagonists for human α_(1C) receptors. This invention is alsorelated to uses of these compounds for lowering intraocular pressure,inhibiting cholesterol synthesis, relaxing lower urinary tract tissue,the treatment of benign prostatic hyperplasia, impotency, cardiacarrhythmia and for the treatment of any disease where antagonism of theα_(1C) receptor may be useful. The invention further provides apharmaceutical composition comprising a therapeutically effective amountof the above-defined compounds and a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structures:

where A is

where each of Y₁, Y₂, Y₃, Y₄ and Y₅ is independently —H; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; —F, —Cl,—Br, or —I; —NO₂; —N₃; —CN; —OR₃, —OCOR₃, —COR₃, —CONHR₃, —CON(R₃)₂, or—COOR₃; or any two of Y₁, Y₂, Y₃, Y₄ and Y₅ present on adjacent carbonatoms can constitute a methylenedioxy group;

where X is S; O; or NR₃;

where R₁ is —H; —NO₂; —CN; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; —N(R₃)₂; —OR₃; —(CH₂)_(p)OR₃;—COR₃; —CO₂R₃; or —CON(R₃)₂;

where R₂ is —H; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C₃-C₁₀cycloalkyl-C₁-C₁₀-alkyl, C₃-C₁₀ cycloalkyl-C₁-C₁₀-monofluoroalkyl orC₃-C₁₀ cycloalkyl-C₁-C₁₀-polyfluoroalkyl; —CN; —CH₂XR₃,—CH₂X(CH₂)_(p)NHR₃, —(CH₂) NHR₃, —CH₂X(CH₂)_(p)N (R₃)₂,—CH₂X(CH₂)_(p)N₃, or —CH₂X(CH₂)_(p)NHCXR₇; or —OR₃;

where each p is independently an integer from 1 to 7;

where each n is independently an integer from 0 to 5;

where each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl;

where R₄ is

where Z is C₂-C₇ alkenyl or alkynyl; CH₂; O; CO; C₂; CONR₃; S; SO; SO₂;or NR₃;

where each D is independently CH₂; O; S; NR₃; CO; or CS;

where W is C═O; C—NOR₃; substituted or unsubstituted phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrroyl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl or benzimidazoyl, where the phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzfurazanyl benzfuranyl or benzimidazolyl is substituted with —H, —F,—Cl, —Br, —I, —NO₂, —CN, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₁-C₇ monofluoroalkyl, straight chained orbranched C₁-C₇ polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl, straight chained or branched C₂-C₇ alkynyl, C₃-C₇ cycloalkyl,C₃-C₇ monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₃-C₇cycloalkenyl, —N(R,)₂, —OR₃, —COR₃, —CO₂R₃, or —CON(R₃)₂;

where each V is independently O; S; CR₅R₇; C(R₇)₂; or NR₇;

where each m is independently an integer from 0 to 3;

where o is an integer from 1 to 3;

where each R is independently —H; —F; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; —N(R₃)₂; —NO₂; CN; —CO₂R₃; or —OR₃;

where R₅ is —H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; phenyl, thiophenyl, pyridyl,pyrrolyl, furanyl, imidazolyl or indolyl; —COOR₃, —COR₃, —CONHR₃, —CN,or —OR₃;

where each R, is independently —H; straight chained or branched C₁-C₇alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl orcycloalkenyl; or —OR₃;

where each R₇ is independently —H; substituted or unsubstituted benzyl,benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl,naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl,benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl,phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl,indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl is substituted with —H, —F, —Cl, —Br, —I,—NO₂, —CN, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₁-C₇ monofluoroalkyl, straight chained or branched C₁-C₇polyfluoroalkyl, straight chained or branched C₂-C₇ alkenyl, straightchained or branched C₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₃-C₇ cycloalkenyl,—N(R₃)₂, —OR₃, —COR₃, —CO₂R₃, or —CON(R₃)₂; substituted or unsubstitutedstraight chained or branched C₃-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; substituted or unsubstituted straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl,where the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl is substituted with —H, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl, benzimidazolyl; and

where R₈ is —H; substituted or unsubstituted benzyl, benzoyl, phenyl,pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinylis substituted with —H, —F, —Cl, —Br, —I, —NO₂,—CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₁-C₇monofluoroalkyl, straight chained or branched C₁-C₇ polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl, straight chained or branchedC₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ monofluorocycloalkyl, C₃-C₇polyfluorocycloalkyl, C₃-C₇ cycloalkenyl, —N(R₃)₂, —OR₃, —COR₃, —CO₂R₃,or —CON(R₃)₂; substituted or unsubstituted straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; substituted orunsubstituted straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl,polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl issubstituted with —H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl,pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl,benzimidazolyl, —N(R₃)₂, —NO₂, —CN, —CO₂R₃, —OR₃;

or a pharmaceutically acceptable salt thereof.

The invention also provides for the (−) and (+) enantiomers of thecompounds described herein.

In those embodiments having the following structure

presently preferred compounds include the following:

In preferred embodiments, the compounds may have the structures:

where V is selected from CR₅R₇ or NR₇ and p is selected from 1-3.

The invention provides for the preferred embodiment having the followingstructures:

The invention further provides that the compound has the followingstructures:

The invention further provides that the compound has the structures:

The invention further provides that the compound has the structures:

In those embodiments having the following structure

presently preferred compounds include the following:

The invention provides for the preferred embodiment having the followingstructure:

In those embodiments having the following structure

presently preferred compounds include the following:

The invention provides for the preferred embodiment having the followingstructure:

where R₅ is selected from —CO₂CH₃ or —H.

The present invention is directed to compounds having the structures:

where A is

where each of Y₁, Y₂, Y₃₁ Y₄ and Y₅ is independently —H; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; —F, —Cl,—Br, or —I; —NO₂; —N₃; —CN; —OR₄, —OCOR₄, —COR₄, —CONHR₄, —CON(R₄)₂, or—COOR₄; or any two of Y₁, Y₂, Y₃, Y₄ and Y₅ present on adjacent carbonatoms can constitute a methylenedioxy group;

where X is S; O; or NR₄;

where B is —H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chainedor branched C₂-C₇ alkenyl; —SCH₂C₆H₄OR₄; —(CH₂)_(n)C₆H₅;—CH₂X(CH₂)_(n)NHR₄; —(CH₂) NHR₄; or —OR₄;

where R₁ is —H; —NO₂; —CN; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; —N(R₄)₂; —OR₄; —(CH₂)_(p)OR₄;—COR₄; —CO₂R₄; or —CON(R₄)₂;

where R₂ is —H; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C₃-C₁₀cycloalkyl-C₃-C₁₀-alkyl, C₃-C₁₀ cycloalkyl-C₁-C₁₀-monofluoroalkyl orC₃-C₁₀ cycloalkyl-C₁-C₁₀-polyfluoroalkyl; —CN; —CH₂XR₄,—CH₂X(CH₂)_(p)NHR₄, —(CH₂)_(n)NHR₄, —CH₂X(CH₂)_(p)N (R₄)₂,—CH₂X(CH₂)_(p)N₃, or —CH₂X(CH₂)_(p)NHCXR₇; or —OR₄;

where each p is independently an integer from 1 to 7;

where each n is independently an integer from 0 to 5;

where R₃ is

where Z is C₂-C₇ alkenyl or alkynyl; CH₂; O; CO; CO₂; CONR₄; S; SO;SO₂.; or NR₄;

where each D is independently CH₂; O; S; NR₄; CO; or CS;

where W is C═O; C═NOR,; substituted or unsubstituted phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl or benzimidazolyl, where the phenyl, Spyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl,imidazolyl, benzfurazanyl, benzfuranyl or benzimidazolyl is substitutedwith —H, —F, —Cl, —Br, —I, —NO₂, —CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₁-C₇ monofluoroalkyl, straightchained or branched C₁-C₇ polyfluoroalkyl, straight chained or branchedC₂-C₇ alkenyl, straight chained or branched C₁-C₇ alkynyl, C₃-C₇cycloalkyl, C₃-C₇ monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl,C₃-C₇ cycloalkenyl, —N(R₄)₂, —OR₄, —COR₄, —CO₂R₄, or —CON(R₄)₂;

where each V is independently O; S; CR₅R₇; C(R₇)₂; or NR₇;

where each m is independently an integer from 0 to 3;

where o is an integer from 1 to 3;

where each R is independently —H; —F; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; —N(R₄)₂; —NO₂; —CN; —CO₂R₄; or —OR₄;

where each R₄ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl;

where R₅ is —H; straight chained-or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; phenyl, thiophenyl, pyridyl,pyrrolyl, furanyl, imidazolyl or indolyl; —COOR₄, —COR₄, —CONHR₄, —CN,or —OR₄;

where each R₆ is independently —H; straight chained or branched C₁-C₇alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl orcycloalkenyl; or —OR₄;

where each R₇ is independently —H; substituted or unsubstituted benzyl,benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl,naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl,benzimidazolyl or 2-keto-1-benzimidazolinyl, where the benzyl, benzoyl,phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl,indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl is substituted with —H, —F, —Cl, —Br, —I,—NO₂, —CN, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₁-C₇ monofluoroalkyl, straight chained or branched C₁-C₇polyfluoroalkyl, straight chained or branched C₂-C₇ alkenyl, straightchained or branched C₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₃-C₇ cycloalkenyl,—N(R₄)₂, —OR₄, —COR₄, —CO₂R₄, or —CON(R₄)₂; substituted or unsubstitutedstraight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; substituted or unsubstituted straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl,where the alkyl; monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl is substituted with —H, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl, benzimidazolyl; and

where R₈ is —H; substituted or unsubstituted benzyl, benzoyl, phenyl,pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl,imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl, where the benzyl, benzoyl, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinylis substituted with -H, —F, —Cl, —Br, —I, —NO₂, —CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₁-C₇monofluoroalkyl, straight chained or branched C₁-C₇ polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl, straight chained or branchedC₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ monofluorocycloalkyl, C₃-C₇polyfluorocycloalkyl, C₃-C₇ cycloalkenyl, —N(R₄)₂, —OR₄, —COR₄, —CO₂R₄,or —CON(R₄)₂; substituted or unsubstituted straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; substituted orunsubstituted straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl or cycloalkenyl, where the alkyl, monofluoroalkyl,polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl issubstituted with —H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl,pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl,benzimidazolyl, —N(R₄)₂, —NO₂, —CN, —CO₂R₄, —OR₄;

or a pharmaceutically acceptable salt thereof.

The invention further provides for the (−) and (+) enantiomers of thecompounds described above.

In those embodiments having the following structure

presently preferred compounds include the following:

The invention provides for the preferred embodiments having thefollowing structures:

In those embodiments having the following structure

presently preferred compounds include the following:

The invention also provides for the following preferred embodimenthaving the structure:

where R₅ is selected from —H or —CO₂CH₃.

The invention further provides for a pharmaceutical compositioncomprising a therapeutically effective amount of any of the compoundsdescribed herein and a pharmaceutically acceptable carrier. In oneembodiment the therapeutically effective amount is an amount from about0.01 mg per subject per day to about 500 mg per subject per day,preferably from about 0.1 mg per subject per day to about 60 mg persubject per day and most preferably from about 1 mg per subject per dayto about 20 mg per subject per day. The therapeutically effective amountis an amount from about 0.01 mg to about 500 mg.

In one preferred embodiment the pharmaceutical carrier may be a liquidand the pharmaceutical composition would be in the form of a solution.In another equally preferred embodiment, the pharmaceutically acceptablecarrier is a solid and the composition is in the form of a powder ortablet. In a further embodiment, the pharmaceutical carrier is a gel andthe composition is in the form of a suppository or cream.

In a preferred embodiment the compound of the pharmaceutical compositionadditionally does not cause a fall in blood pressure at dosageseffective to alleviate benign prostatic hyperplasia. In a furtherembodiment the compound of the pharmaceutical composition additionallydoes not cause a fall in blood pressure in rats at a dosage of 10micrograms of compound per kilogram per rat.

The invention provides a method of treating a subject suffering frombenign prostatic hyperplasia which comprises administering to thesubject one of the compounds described herein effective to treat benignprostatic hyperplasia. The invention further provides that the compoundadditionally does not cause a fall in blood pressure at dosageseffective to alleviate benign prostatic hyperplasia. In one embodimentthe compound additionally does not cause a fall in blood pressure inrats at a dosage of 10 micrograms of compound per kilogram of rat. Inone preferred embodiment the compound effects treatment of benignprostatic hyperplasia by relaxing lower urinary tract tissue and inparticular where lower urinary tract tissue is urethral smooth muscle.

The invention further provides a method of treating a subject sufferingfrom high intraocular pressure which comprises administering to thesubject one of the compounds described herein effective to lowerintraocular pressure.

The invention further provides a method of treating a subject sufferingfrom a disorder associated with high cholesterol which comprisesadministering to the subject one of the compounds described hereineffective to inhibit cholesterol synthesis.

The invention also provides a method of treating a disease which issusceptible to treatment by antagonism of the α_(1C) receptor whichcomprises administering to -the subject one of the compounds describedherein effective to treat the disease.

The invention further provides a method of treating a subject sufferingfrom impotency which comprises administering to the subject one of thecompounds described herein effective to treat impotency.

The invention further provides a method of treating a subject sufferingfrom sympathetically mediated pain which comprises administering to thesubject one of the compounds described herein effective to treatsympathetically mediated pain.

The invention provides a method of treating a subject suffering fromcardiac arrhythmia which comprises administering to the subject one ofthe compounds described herein effective to treat cardiac arrhythmia.

The invention provides a method of treating a subject suffering frombenign prostatic hyperplasia which comprises administering to thesubject one of the compounds described herein in combination with a 5alpha-reductase inhibitor effective to treat benign prostatichyperplasia. In one preferred embodiment the 5-alpha reductase inhibitoris finasteride.

A pharmaceutical composition comprising a therapeutically effectiveamount one of the compounds described herein in combination with atherapeutically effective amount of finasteride and a pharmaceuticallyacceptable carrier. In one preferred embodiment the therapeuticallyeffective amount of one of the compounds described herein is an amountfrom about 0.01 mg to about 500 mg and the therapeutically effectiveamount of the finasteride is about 5 mg. In a more preferred embodimentthe therapeutically effective amount one of the compounds describedherein is an amount from about 0.1 mg to about 60 mg and thetherapeutically effective amount of finasteride is about 5 mg. In afurther embodiment of the invention the therapeutically effective amountof the one of the compounds described herein is an amount from about 1mg to about 20 mg and the therapeutically effective amount offinasteride is about 5 mg.

The invention further provides a method of relaxing lower urinary tracttissue which comprises contacting the lower urinary tract tissue with anamount of one of the compounds described herein effective to relax lowerurinary tract tissue. In one embodiment the lower urinary tract tissueis urethral smooth muscle.

The invention provides a method of relaxing lower urinary tract tissuein a subject which comprises administering to the subject an amount ofone of the compounds described herein effective to relax lower urinarytract tissue. In one preferred embodiment the lower urinary tract tissueis urethral smooth muscle.

The invention provides for the use of the compounds described herein forthe preparation of a pharmaceutical composition for lowering intraocularpressure, inhibiting cholesterol synthesis, and the treatment of: benignprostatic hyperplasia, impotency, cardiac arrhythmia and any diseasewhere antagonism of the aic receptor may be useful. The inventionprovides for the use of the compounds described herein for thepreparation of a pharmaceutical composition for relaxing lower urinarytract tissue and in particular urethral smooth muscle. The inventionfurther provides for the use of any of compounds described herein forthe preparation of a pharmaceutical composition, where the compoundadditionally does not cause a fall in blood pressure at dosageseffective to lower intraocular pressure, to inhibit cholesterolsynthesis, and for the treatment of: benign prostatic hyperplasia,impotency, cardiac arrhythmia and any disease where antagonism of theα_(1C) receptor may be useful.

Furthermore the invention provides that the compound used in thepreparation of the pharmaceutical composition additionally does notcause a fall in blood pressure in rats at a dosage of 10 micrograms ofcompound per kilogram per rat.

The invention provides for the use of the compounds described herein inthe preparation of a medicament for lowering intraocular pressure,inhibiting cholesterol synthesis, and for the treatment of: benignprostatic hyperplasia, impotency, cardiac arrhythmia and any diseasewhere antagonism of the α_(1C) receptor may be useful. The inventionprovides for the use of the compounds described herein in thepreparation of a medicament for relaxing lower urinary tract tissue andin particular urethral smooth muscle. The invention further provides forthe use of any of compounds described herein in the preparation of amedicament, where the compound additionally does not cause a fall inblood pressure at dosages effective to lower intraocular pressure, toinhibit cholesterol synthesis, and for the treatment of: benignprostatic hyperplasia, impotency, cardiac arrhythmia and any diseasewhere antagonism of the α_(1C) receptor may be useful. The inventionfurther provides that the compound in the medicament additionally doesnot cause a fall in blood pressure in rats at a dosage of 10 microgramsof compound per kilogram per rat.

The invention provides for a drug which is useful for loweringintraocular pressure, inhibiting cholesterol synthesis, and thetreatment of: benign prostatic hyperplasia, impotency, cardiacarrhythmia and any disease where antagonism of the α_(1C) receptor maybe useful, the effective ingredient of the said drug being any of thecompounds described herein. The invention further provides the drugdescribed herein additionally does not cause a fall in blood pressure atdosages effective to lower intraocular pressure, to inhibit cholesterolsynthesis, and for the treatment of: benign prostatic hyperplasia,impotency, cardiac arrhythmia and any disease where antagonism of theα_(1C) receptor may be useful. The invention further provides that thedrug additionally does not cause a fall in blood pressure in rats at adosage of 10 micrograms of compound per kilogram per rat.

The invention provides for a drug which is useful for relaxing lowerurinary tract tissue and in particular urethral smooth muscle, theeffective ingredient of the drug being any of the compounds describedherein. The invention further provides the drug which is useful forrelaxing lower urinary tract tissue additionally does not cause a fallin blood pressure at dosages effective to relax lower urinary tracttissue. The invention further provides that the drug which is useful forrelaxing lower urinary tract tissue additionally does not cause a fallin blood pressure in rats at a dosage of 10 micrograms of compound perkilogram per rat.

The invention also provides for the (−) and (+) enantiomers of allcompounds of the subject application described herein. Included in thisinvention are pharmaceutically acceptable salts and complexes of all ofthe compounds described herein. The salts include but are not limited tothe following acids and bases. The following inorganic acids;hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid,sulfuric acid and boric acid. The organic acids; acetic acid,trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid,glycolic acid, lactic acid and mandelic acid. The following inorganicbases; ammonia, hydroxyethylamine and hydrazine. The following organicbases; methylamine, ethylamine, propylamine, dimethylamine,diethylamine, trimethylamine, triethylamine, ethylenediamine,hydroxyethylamine, morpholine, piperazine and guanidine. This inventionfurther provides for the hydrates and polymorphs of all of the compoundsdescribed herein.

The invention also provides a pharmaceutical composition comprising atherapeutically effective amount of the compounds described above and apharmaceutically acceptable carrier. In the subject invention a“therapeutically effective amount” is any amount of a compound which,when administered to a subject suffering from a disease against whichthe compounds are effective, causes reduction, remission, or regressionof the disease. In one embodiment the therapeutically effective amountis an amount from about 0.01 mg per subject per day to about 500 mg persubject per day, preferably from about 0.1 mg per subject per day toabout 60 mg per subject per day and most preferably from about 1 mg persubject per day to about 20 mg per subject per day. In the practice ofthis invention the “pharmaceutically acceptable carrier” is anyphysiological carrier known to those of ordinary skill in the art usefulin formulating pharmaceutical compositions.

The invention also provides for pharmaceutical composition comprising atherapeutically effective amount of the any of the compounds describedherein in combination with a therapeutically effective amount offinasteride and a pharmaceutically acceptable carrier. In one embodimentthe pharmaceutical composition is a therapeutically effective amountfrom about 0.01 mg per subject per day to about 500 mg per subject perday of any one of the compounds described herein and a therapeuticallyeffective amount of the finasteride of about 5 mg per subject per day. Amore preferred embodiment of the pharmaceutical composition is atherapeutically effective amount from about 0.1 mg per subject per dayto about 60 mg per subject per day of any one of the compounds describedherein and a therapeutically effective amount of the finasteride ofabout 5 mg per subject per day. The most preferred embodiment of thepharmaceutical composition is a therapeutically effective amount fromabout 1 mg per subject per day to about 20 mg per subject per day of anyone of the compounds described herein and a therapeutically effectiveamount of the finasteride of about 5 mg per subject per day.

In one preferred embodiment the pharmaceutical carrier may be a liquidand the pharmaceutical composition would be in the form of a solution.In another equally preferred embodiment, the pharmaceutically acceptablecarrier is a solid and the composition is in the form of a powder ortablet. In a further embodiment, the pharmaceutical carrier is a gel andthe composition is in the form of a suppository or cream. In a furtherembodiment the compound may be formulated as a part of apharmaceutically acceptable transdermal patch.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

The invention further provides a method of treating a subject sufferingfrom benign prostatic hyperplasia which comprises administering to thesubject an amount of the one the compounds described above effective totreat benign prostatic hyperplasia.

The invention also provides a method of treating a subject sufferingfrom high intraocular pressure which comprises administering to thesubject an amount of any of the compounds described above effective tolower intraocular pressure.

This invention also provides a method of treating a subject suffering adisorder associated with high cholesterol which comprises administeringto the subject an amount of any of the compounds described aboveeffective to inhibit cholesterol synthesis.

This invention also provides a method of treating a disease which issusceptible to treatment by antagonism of the α_(1C) receptor whichcomprises administering to the subject an amount of any the compoundsdescribed above effective to treat the disease.

This invention also provides a method of treating a subject sufferingfrom impotency which comprises administering to the subject an amount ofany of the compounds described above effective to treat impotency.

This invention also provides a method of treating a subject sufferingfrom sympathetically mediated pain which comprises administering to thesubject an amount of any of the compounds described above effective totreat sympathetically mediated pain.

This invention also provides a method of treating a subject sufferingfrom cardiac arrhythmia which comprises administering to the subject anamount of any of the compounds described above effective to treatcardiac arrhythmia.

This invention also provides a method of treating a subject sufferingfrom benign prostatic hyperplasia which comprises administering to thesubject an amount of any of the compounds described above in combinationwith a 5 alpha-reductase inhibitor effective to treat benign prostatichyperplasia. The 5-alpha reductase inhibitor is finasteride. The dosageadministered to the subject is about 0.01 mg per subject day to 50 mgper subject per day of finasteride in combination with an α_(1C)antagonist. A preferred dosage administered to the subject is about 0.2mg per subject per day to 10 mg per subject per day of finasteride incombination with an α_(1C) antagonist. A more preferred dosageadministered to the subject is about 1 mg per subject per day to 7 mgper subject per day of finasteride in combination with an α_(1C)antagonist. The most preferred dosage administered to the subject isabout 5 mg per subject per day of finasteride in combination with anα_(1C) antagonist.

One skilled in the art will readily appreciate that appropriatebiological assays will be used to determine the therapeutic potential ofthe claimed compounds for the treating the above noted disorders.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

Experimental Details

For Examples 1-17 Scheme 1 describes the general synthetic preparation.All NMRs were obtained using a 300 MHz GE QEPLUS NMR machine.

EXAMPLE 1

1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl)}carboxamido pyrimidine.

a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidonemonohydrate hydrochloride (15.0 g, 0.0976 mol) and AlCl₃ (130 g, 0.976mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4hours. The mixture was cooled to room temperature, poured into ice (300g) and water (50 mL), and filtered. The solid was washed with tolueneand dried to afford 19.2 g (72%) of an off-white solid, which wascharacterized spectroscopically.

b. 3-(4,4-Diphenylpiperidin-1-yl)propionitrile. To a suspension of4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5mL) was added Et₃N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile(0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution was stirred at roomtemperature under argon for 15 min and then concentrated. Water wasadded, and the mixture was extracted with EtOAc (3×10 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated to give 170 mg(87%) of a tan solid, which was characterized spectroscopically and usedin the next reaction without purification.

c. 3-(4,4-Diphenylpiperidin-1-yl)propylamine. To a stirred solution of3-(4,4-diphenylpiperidin-1-yl)propionitrile (2.00 g, 6.89 mmol) inanhydrous THF (20 mL) under argon was added a solution of BH₃ in THF(1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature. The mixture wasrefluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl(6 N, 50 mL) was added and stirring was continued for 1 hour. Themixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted withCH₂Cl₂ (3×10 mL), dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography (SiO₂, EtOAc-MeOH-isopropylamine 9:1:0to 4:1:0.2) to give 1.35 g (66%) of tan solid, which was characterizedspectroscopically.

d. 2-(4-Methoxybenzyl)-2-thiopseudourea hydrochloride.

To a well-stirred suspension of thiourea (7.6 g, 0.1 mol) in THF (50 mL)at 0° C., 4-methoxybenzyl chloride (16 g, 0.1 mol) was added in 10 minand the mixture was allowed to warm to room temperature. After 2 hoursthe mixture was heated to 65° C. and kept at that temperature for 5hours. It was cooled to room temperature and diluted with diethyl ether(200 mL). The white precipitate formed was filtered and dried (22.5 g,96%); m. p. 161-163° C.

e. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate.A mixture of4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g,0.11 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at roomtemperature for 48 hours. The white solid, methyl2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was filtered, washedwith 2-propanol (2×50 mL) and dried (21.80 g, 93%).

f. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine. A mixture of methyl2-{(4-nitrophenyl)methylene}-3-oxobutyrate (8.96 g, 0.04 mol),2-(4-methoxybenzyl)-2-thiopseudourea hydrochloride (9.28 g, 0.04 mol),and NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and heated at70-75° C. for 4.5 hours. The mixture was cooled, poured into ice-water(300 mL), extracted with EtOAc (2×400 mL). The combined EtOAc extractswere washed with 10% NaHCO₃ solution (2×60 mL), brine (100 mL), anddried (MgSO₄). Solvent was evaporated and the crude product was purifiedby flash column chromatography on silica gel using 10% through 30% EtOAcin hexane as the gradient eluent, to leave the product as an oil, whichon trituration with EtOAc/hexane became a yellow solid (11.4 g, 66.7%);m.p. 138-139° C.; ¹H-NMR (CDCl₃): δ 2.15 (s, 3H), 3.62 (s, 3H), 3.72 (s,3H), 4.05, 5.78 (s, d, J=3 Hz, 1 H), 4.08, 4.20 (AB q, J=12.5 Hz, 2H),4.21, 6.40 (s, d, J=3 Hz, 1H), 6.66 (2 d, J=8.5 Hz, 2H), 7.08 (2 d,J=8.5 Hz, 2H), 7.37 (2 d, J=8.8 Hz, 2H), 8.7 (2 d, J=8.8 Hz, 2H); Anal.Calcd. for C₂, H₂₁N₃O₅S: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.02; H,4.93; N, 9.77.

g. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred mixture of 1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine (4.5 g, 0.0105 mol), NaHCO₃ (3.69 g, 0.044mol), CH₂Cl₂ (200 mL), and water (50 mL) at 0-5° C., 4-nitrophenylchloroformate (2.4 g, 0.0119 mol) was added in 5 min and the mixture wasallowed to warm to room temperature. After 10 hours, the TLC analysis ofthe reaction mixture showed the presence of a small amount of startingpyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, 0.0032mol) was added and the stirring continued for an additional 4 hours. Thetwo layers were separated, the CH₂Cl₂ layer was washed with saturatedaqueous NaHCO₃ solution (3×50 mL), dried (MgSO₄), and the solventevaporated. The residue was recrystallized from CH₂Cl₂ and hexane togive the product as white crystals (5.5 g, 88.4%); m.p. 156-157° C.;¹H-NMR (CDCl₃): δ 2.53 (s, 3H), 3.70 (s, 3 H), 3.81 (s, 3H), 4.06, 4.36(AB q, J=13.5 Hz, 2H), 6.30 (s, 1H), 6.78 (d, J=8.7 Hz, 2H), 7.17 (d,J=8.5 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.97 (d,J 8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); Anal. Calcd. for C₂1H₂₄N₄0₉S: C,56.75; H, 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.

h. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)prop-yl]}carboxamidopyrimidine.

To a stirred solution of 1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) inanhydrous THF (10 mL) at room temperature under argon atmosphere, asolution of 3-[4,4-diphenylpiperidin-1-yl]propylamine (0.441 g, 1.5mmol, 1.5 eq) in THF (5 mL) was added and the stirring continued for 1hours. Solvent was evaporated from the reaction mixture and the residuewas redissolved in CH₂Cl₂ (50 mL), washed with 5% NaHCO₃ (3×25 mL),brine (50 mL), and dried (MgSO₄). Solvent was evaporated and the residuewas purified by flash chromatography on silica gel using 10% methanol inEtOAc as the eluent to give the desired product as an oil, which ontrituration with hexane and drops of EtOAc became a white powder (0.32g, 43%); m.p. 79-80° C.; ¹H-NMR (CDCl₃): δ 1.61-1.82 (m, 4H), 2.27 (s,3H), 2.30-2.51 (m, 8H), 3.19-3.36 (m, 1H), 3.42-3.60 (m, 1H), 3.68 (s,3H), 3.76 (s, 3H), 3.95, 4.22 (AB q, J=13.6 Hz, 2H), 6.16 (s, 1H), 6.70(d, J=8.6 Hz, 2H), 7.04 (d, J=8.6 Hz, 2H), 7.11-7.29 (m, 12H), 7.68 (brt, 1 H, NH), 7.91 (d, J=8.8 Hz, 2H); Anal. Calcd. for C₄₂H₄₅N₅O₆S.0.33CH₂Cl₂: C, 65.52; H, 5.93; N, 9.03. Found: C, 65.52; H, 6.01; N, 9.20.

EXAMPLE 2

1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine.

a. 3-(4-Phenylpiperidin-1-yl)propionitrile. Acrylonitrile (3.1 mL, 44mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.0 g, 18mmol) in EtOH (40 mL) and the mixture was stirred at room temperaturefor 1.5 hours. The volatiles were removed to give 3.8 g of pure product(brown oil, 99%), which was characterized spectroscopically.

b. 3-(4-Phenylpiperidin-1-yl)propylamine. To a stirred solution of3-(4-phenylpiperidin-1-yl)propionitrile (5.1 g, 24 mmol) in anhydrousTHF (20 mL) under argon was added a solution of BH₃ in THF (1.0 M, 83mL, 83 mmol, 3.5 eq) at room temperature. The mixture was refluxed for4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 130 mL)was added and stirring was continued for 2 hours at 50-70° C. Themixture was basified to pH 9 by addition of 6 N aq. NaOH and extractedwith EtOAc (100 mL) and CH₂Cl₂ (3×100 mL). The combined organic extractswere dried (MgSO₄) and concentrated. The residue was dissolved in CH₂Cl₂(20 mL) and treated with HCl in ether (1.0 M, 50 mL). The solvents wereremoved, ether (250 mL) was added, the mixture was filtered, and thefilter cake was washed with ether. Water (60 mL) was added to theresulting white solid, the pH was adjusted to 10-11 with 1 N NaOH, andthe aqueous phase was extracted with CH₂Cl₂ (3×50 mL). The combinedextracts were dried (MgSO₄) and the solvents evaporated to give 4.5 g(87%) of pure product (light brown solid), which was characterizedspectroscopically.

c. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine. This compound was prepared from1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.77 g, 1.3 mmol),3-[4-phenylpiperidin-1-yl]propylamine (0.34 g, 1.56 mmol, 1.2 eq) andpurified using similar conditions described in Example 1 (0.63 g, 72-;);m.p. 123-124° C.; ¹H-NMR (CDCl₃): δ 1.65-2.10 (m, 8H), 2.41 (s, 3H),2.41-2.55 (m, 3H), 2.99-3.06 (m, 2H), 3.2-3.35 (m, 1H), 3.45-3.60 (m,1H), 3.67 (s, 3H), 3.75 (s, 3H), 4.10, 4.33 (AB q, J=13.6 Hz, 2H), 6.19(s, 1H), 6.71 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.6 Hz, 2H), 7.20-7.34 (m,7H), 7.97 (br t, 1 H, NH), 7.97 (d, J=8.8 Hz, 2H); Anal. Calcd. forC₃₆H₄₁N₅O₆. 0.25 CH₂Cl₂: C, 62.82; H, 6.04; N, 10.11. Found: C, 62.54;H, 6.13; N, 10.03.

EXAMPLE 3

1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl) pyrimidine.

a. 3-(4-Cyano-4-phenylpiperidinlyl)propylamine.4-Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5 mmol) was addedto water (100 mL), and the solution was basified to pH 10-11 by additionof 6 N aqueous NaOH. The mixture was extracted with CH₂Cl₂ (3×100 mL).The combined organic extracts were dried (MgSO₄) and concentrated. Tothe residue were added 3-bromopropylamine hydrobromide (4.92 g, 22.5mmol), anhydrous K₂CO₃ (3.42 g, 24.8 mmol, 1.10 eq), and 1,4-dioxane(100 mL). The mixture was stirred at reflux for 24 hours under a CaSO₄drying tube. The solvent was evaporated, and the product was purified byflash chromatography (SiO₂, CHCl₃/MeOH/2 M NH₃ in MeOH (100:8:4 to100:20:8) to give 3.23 g (59%) of colorless oil, which was characterizedspectroscopically.

b.1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,6-dihydro-5-methoxycarbonyl-2[{(4-methoxy-phenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl) pyrimidine.

This compound was prepared from 1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl) methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimi dine (0.592 g, 1mmol), 3-[4-cyano-4-phenyl piperidin-1-yl]propylamine (0.292 g, 1.2mmol, 1.2 eq) and purified using similar conditions described in Example1 (0.445 g, 64%); m.p. 143-144° C.; ¹H-NMR (CDCl₃): δ 1.70-1.86 (m, 2H),2.02-2.09 (m, 4H), 2.38 (s, 3H), 2.41-2.56 (m, 4H), 2.95-3.02 (m, 2H),3.24-3.40 (m, 1H), 3.42-3.58 (m, 1H), 3.68 (s, 3H), 3.76 (s, 3H), 4.08,4.23 (AB q, J=13.5 Hz, 2H), 6.23 (s, 1H), 6.72 (d, J=8.6 Hz, 2H), 6.94(br t, 1 H, NH), 7.08 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H),7.33-7.49 (m, 5H), 7.94 (d, J=8.8 Hz, 2H); Anal. Calcd. for C₃₇H₄₀N₆O₆S:C, 63.78; H, 5.79; N, 12.06. Found: C, 63.86; H, 5.90; N, 11.92.

EXAMPLE 4

1,6-Dihydro-5-methoxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine.

a. 4-Mothoxycarbonyl-4-phenylpiperidine. To a stirred solution of H₂SO₄(16 mL) in MeOH (400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methylbenzenesulfonate (37.7 g, 0.1 mole) was added and the mixture wasstirred and refluxed for 8 hours. Excess methanol was evaporated atreduced pressure and the residue was poured into a mixture of ice and 6N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH andextracted with CH₂Cl₂ (3×150 mL). The combined CH₂Cl₂ extracts weredried (MgSO₄) and the solvent evaporated to leave the desired product asa viscous oil. The product (20.2 g, 92%) was used without furtherpurification.

b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylazine.

A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol),3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate(13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200mL) was stirred and refluxed for 24 hours. Dioxane was evaporated atreduced pressure, the residue was treated with ice-cold 6 N NaOH (400mL) and extracted with CH₂Cl₂ (4×120 mL). Solvent was evaporated fromthe combined dried (K₂CO₃) extracts and the residue was purified bycolumn chromatography on silica gel using CHCl₃/MeOH/2 M NH₃ in MeOH(20:2:1) as the eluent to afford the product as a viscous oil (7.8 g,72%).

c.1,6-Dihydro-5-methoxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine.This compound was prepared from 1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine (1.0 g, 1.69 mmol),3-[4-methoxycarbonyl-4-phenyl piperidin-1-yl]propylamine (0.56 g, 2.03mmol, 1.2 eq) and purified using similar conditions described in Example1 (1.085 g, 88%); m.p. 140-141° C.; ¹H-NMR (CDCl₃): δ 1.62-1.74 (m, 2H),1.82-2.18 (m, 4H), 2.21 (s,. 3H), 2.35-2.58 (m, 4H), 2.75-2.89 (m, 2H),3.18-3.30 (m, 1H), 3.42-3.58 (m, 1H), 3.61 (s, 3H), 3.66 (s, 3H), 3.75(s, 3H), 3.91, 4.15 (AB q, J=13.6 Hz, 2H), 6.14 (s, 1H), 6.69 (d, J=8.6Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 7.20-7.37 (m, 7H), 7.56 (br t, 1 H,NH), 7.90 (d, J=8.8 Hz, 2H); Anal. Calcd. for C₃₈H₄₃N₅O₈S: C, 62.54; H,5.94; N, 9.60. Found: C, 62.41; H, 6.06; N, 9.34.

EXAMPLE 5

5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)1-{N-[3-(4,4-diphenyl-piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-thioxo-pyrimidine.

To a stirred solution of1,6-dihydro-6-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}carboxamidopyrimidine (0.14 g, 0.187 mmol) and ethanethiol (0.5 mL) inCH₂Cl₂ (5 mL) at 5° C. under argon, TFA (0.5 mL) was added and themixture was allowed to warm to room temperature. After 3 hours, solventswere evaporated completely, the residue was redissolved in EtOAc (10mL), washed with 5% NaHCO₃ (5×1 mL) and dried (MgSO₄). Solvent wasevaporated and the residue was purified by column chromatography using1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product wascrystallized from hexane and EtOAc (0.096 g, 82%); m.p. 130-131° C.;¹H-NMR (CDCl₃): δ 1.65-1.80 (m, 2H), 2.31 (s, 3H), 2.31-2.49 (m, 10H),3.25-3.55 (m, 2H), 3.76 (s, 3H), 7.01 (s, 1H), 7.09-7.29 (m, 6H), 7.41(d, J=8.2 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 9.76 (br t, 1 H, NH); Anal.Calcd. for C₃₄H₃₇N₅O₆S.0.3 H₂O: C, 64.50; H, 5.89; N, 11.06. Found: C,64.45; H, 6.05; N, 10.87.

EXAMPLE 6

5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4-phenyl-piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-thioxo-pyrimidine.

This compound was prepared from1,6-dihydro-3-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamido-6-methoxycarbonyl-2-[{(4-methoxyphenyl) methyl}thio]-6-(4-nitrophenyl)-4-methylpyrimidine (0.15 g, 0.223 mmol) using the proceduredescribed in Example 5 and purified by flash column chromatography(0.102 g, 83%); m.p. 134-135° C.; ¹H-NMR (CDCl₃): b 1.72-1.94 (m, 4H),1.96-2.11 (m, 2 H), 2.36 (s, 3H), 3.0-3.09 (m, 2H), 3.32-3.49 (m, 2 H),3.76 (s, 3H), 7.06 (s, 1H), 7.17-7.30 (m, 6H), 7.42 (d, J=8.7 Hz, 2H),8.11 (d, J=8.8 Hz, 2H), 9.80 (br t, 1 H, NH); Anal. Calcd. forC₂₈H₃₃N₅O₅S: C, 60.96; H, 6.03; N, 12.70. Found: C, 60.63; H, 5.78; N,12.55.

EXAMPLE 7

1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxopyrimidine.

This compound was prepared from 1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,6-dihydro-6-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-6-(4-nitrophenyl)-4-methylpyrimidine (0.15 g, 0.215 mmol) using theprocedure described in Example 5 and purified by flash columnchromatography (0.118 g, 95%); m.p. 137-138° C.; ¹H-NMR (CDCl₃): b1.69-1.85 (m, 2H), 2.07-2.20 (m, 4H), 2.37 (s, 3H), 2.37-2.60 (m, 4H),2.96-3.06 (m, 2H), 3.31-3.86 (m, 2H), 3.76 (s, 3H), 7.09 (s, 1H),7.31-7.49 (m, 7H), 7.92 (br s, 1 H, NH), 8.12 (d, J=8.8 Hz, 2H), 9.84(br t, 1 H, NH); Anal. Calcd. for C₂₉H₃₂N₆O₅S: C, 60.53; H, 5.74; N,14.49. Found: C, 60.53; H, 5.74; N, 14.48.

EXAMPLE 8

5-Methoxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxopyrimidine

This compound was prepared from 1,6-dihydro-6-methoxycarbonyl-3-{N-[4-methoxycarbonyl-phenyl-piperidin-1-yl]propyl}carboxamido-2-[{(4-methoxyphenyl)methyl}thio]-6-(4-nitrophenyl)-4-methylpyrimidine (0.730 g, 1 mmol)using the procedure described in Example 5 and purified by flash columnchromatography (0.57 g, 94%); m.p. 135-136° C.; ¹H-NMR (CDCl₃): δ1.62-2.13 (m, 6H), 2.32 (s, 3H), 2.33-2.39 (m, 4H), 2.76-2.84 (m, 2H),3.34-3.43 (m, 2H), 3.61 (s, 3H), 3.75(s, 3H), 7.04 (s, 1H), 7.21-7.35(m, 5H), 7.40 (d, J=8.6 Hz, 2H), 7.82 (br s, 1 H, NH), 8.10 (d, J=8.9Hz, 2H), 9.76 (br t, 1 H, NH); Anal. Calcd. for C₃₀H₃₅N₅O₇S: C, 59.10;H, 5.79; N, 11.49. Found: C, 59.08; H, 5.91; N, 11.31.

EXAMPLE 9

1-{N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxopyrimidine.

a. 4-(4-Methoxyphenyl)-4-phenylpiperidine. 4-Hydroxy-4-phenylpiperidine(5.00 g, 28.2 mmol) was added to a suspension of AlCl₃ (18.8 g, 0.141mol, 5.00 eq) in anhydrous anisole (100 mL). The mixture was stirred atroom temperature for 1 hours and then heated to 50° C. for 3.5 hours. Itwas cooled to room temperature and poured cautiously into ice-water. Themixture was basified to pH 11 by addition of 6 N aqueous NaOH, andextracted with EtOAc (3×75 mL). The combined organic extracts wereapplied directly to a flash chromatography column, which was eluted withCH₂Cl₂/0.67 M NH₃ in MeOH (4:1) to afford 1.683 g (22%) of light yellowoil, which was characterized spectroscopically.

b. 3-[4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile.Acrylonitrile (1.03 mL, 15.7 mmol, 2.50 eq) was added at 0° C. to asolution of 4-(4-methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol)in EtOH (20 mL) and the resulting solution was stirred for 1.5 hours atroom temperature. After removal of the solvent, the residue was purifiedby flash chromatography (SiO₂, EtOAc—CHCl₃ 1:3) to give 1.41 g (70%) ofcolorless oil, which was characterized spectroscopically.

c. 3-[4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl]propylamine. To astirred solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile (1.41 g, 4.40 mmol) in anhydrous THF (10 mL) under argon wasadded a solution of BH₃ in THF (1.0 M, 11.0 mL, 2.5 eq) at roomtemperature. The mixture was refluxed for 4.5 hours and then cooled toroom temperature. Aqueous HCl (6 N, 15 mL) was added and stirring wascontinued for 2 h at 55-60° C. The mixture was basified to pH 9 byaddition of 6 N aq. NaOH and extracted with CH₂Cl₂ (3×75 mL). Thecombined organic solutions were dried (MgSO₄) and concentrated. Theresidue was dissolved in CH₂Cl₂ (10 mL) and treated with HCl in ether(1.0 M, 9.0 mL, 2.0 eq). The solvents were removed, ether (30 mL) wasadded, the mixture was filtered, and the filter cake was washed withether (2×10 mL). Water (20 mL) was added to the resulting white solid,the pH was adjusted to 10 with 1 N NaOH, and the aqueous phase wasextracted with CH₂Cl₂ (3×40 mL). The combined organic extracts weredried (MgSO₄) and concentrated to give 610 mg (43%) of white solid,which was characterized spectroscopically.

d. 1-{N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxopyrimidine.

To a stirred mixture of 1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) andK₂CO₃ (0.276 g, 2 mmol) in anhydrous THF (10 mL) at room temperatureunder argon atmosphere, a solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propylamine (0.390 g, 1.2 mmol, 1.2 eq) in THE (10 mL)was added and the stirring was continued for 1 hour. Solvent wasevaporated from the reaction -mixture and the residue was redissolved inCH₂Cl₂ (50 mL), washed with 5% NaHCO₃ (3×25 mL), brine (50 mL), anddried (MgSO₄). The CH₂Cl₂ solution was filtered and cooled to 5° C. Tothis, ethanethiol (0.5 mL) and TFA (0.5 mL) were added and the mixturewas stirred and allowed to warm to room temperature. After 3 hours,solvents were evaporated completely, the residue was redissolved inEtOAc (10 mL), washed with 5% NaHCO₃ (5×1 mL), and dried (MgSO₄).Solvent was evaporated and the residue was purified by columnchromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent.The oily product was crystallized from hexane and EtOAc (0.41 g, 62%);m.p. 120-121° C.; ¹H-NMR (CDCl₃): δ 1.60-1.80 (m, 2H), 2.31 (s, 3H),2.31-2.51 (m, 8H), 3.32-3.43 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 6.77(d, J=8.8 Hz, 2H), 7.02 (s, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.20-7.27 (m,6H), 7.41 (d, J=8.6 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 9.76 (br t, 1 H,2H); Anal. Calcd. for C₃₅H₃₉N₅O₆S: C, 63.91; H, 5.98; N, 10.65. Found:C, 64.19; H,6.22; N, 10.36.

EXAMPLE 10

a. 4-Ethoxycarbonyl-4-phenylpiperidine. To a stirred solution of H₂SO₄(1.62 g, 16.56 mmol) in EtOH (200 mL), 4-phenyl-4-piperidine-carboxylicacid 4-methyl benzenesulfonate (25 g, 66.23 mmol) was added and themixture was stirred and refluxed for 12 hours. Excess ethanol wasevaporated at reduced pressure and the residue was poured into a mixtureof ice and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 NNaOH and extracted with CH₂Cl₂ (3×100 mL). The combined CH₂Cl₂ extractswere dried (MgSO₄) and the solvent evaporated to leave the desiredproduct as a colorless viscous oil, the ¹H-NMR showed it to be pure(14.68 g, 95%) and was used without any further purification.

b. 3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl) propylamine.

A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol),3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassiumcarbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane wasevaporated at reduced pressure, the residue was treated with ice-cold 6N NaOH (400 mL) and extracted with CH₂Cl₂ (4×120 mL) Solvent wasevaporated from the combined dried (K₂CO₃) CH₂Cl₂ extracts and theresidue was purified by column chromatography on silica gel usingCHCl₃/MeOH/2 M NH₃ in MeOH (20:2:1) as the eluent to afford the productas a viscous oil (24.2 g, 83.3%).

c. 1-{N-[3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetra-hydro-2-thioxopyrimidine.This compound was prepared from1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol), K₂CO₃ (0.276 g, 2 mmol),3-[4-ethoxycarbonyl-4-phenyl piperidin-1-yl]propylamine (0.350 g, 1.2mmol, 1.2 eq), ethanethiol (0.5 mL), and TFA (0.5 mL) using theprocedure described in Example 10 and purified by flash columnchromatography (0.295 g, 47%); m.p. 125-126° C.; ¹H-NMR (CDCl₃): δ 1.13(t, J=7 Hz, 3H), 1.62-1.80 (m, 2H), 1.87-2.0 (m, 2H), 2.06-2.18 (m, 2H),2.31 (s, 3H), 2.34-2.39 (m, 2H), 2.50-2.55 (m, 2H), 2.79-2.83 (m, 2H),3.30-3.51 (m, 2H), 3.74 (s, 3H), 4.07 (q, J=7 Hz, 2H), 7.03 (s, 1H),7.18-7.36 (m, 6H), 7.40 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 2H), 9.78(br t, 1 H, NH); Anal. Calcd. for C₃₁H₃₇N₅O₇S: C, 59.70; H, 5.98; N,11.23. Found: C, 59.55; H, 5.99; N, 11.43.

EXAMPLE 11

1,6-Dihydro-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}carboxamido-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)pyrimidine.To a stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyri midine (0.940 g,2 mmol) and K₂CO₃ (0.552 g, 4 mmol) in anhydrous THF (20 mL) at roomtemperature under argon atmosphere, a solution of 3[4,4-diphenylpiperidin-1-yl]propylamine (0.882 g, 3 mmol, 1.5 eq) in THF(5 mL) was added and the stirring was continued for 1 hour. Solvent wasevaporated from the reaction mixture, the residue was redissolved inCH₂Cl₂ (50 mL), washed with 5% NaHCO₃ (3×25 mL), brine (50 mL), anddried (MgSO₄). Solvent was evaporated and the residue was purified byflash chromatography on silica gel using 10% methanol in EtOAc as theeluent to give the desired product as an oil, which on trituration withhexane and drops of EtOAc became a white powder (1.10 g, 88%); m.p.95-96 ° C.; ¹H-NMR (CDCl₃): δ 1.61-1.71 (m, 2H), 2.26-2.33 (m, 2H), 2.38(s, 3H), 2.39-2.50 (m, 8H), 3.20-3.41 (m, 2H), 3.65 (s, 3H), 3.89 (s,3H), 6.65 (s, 1H), 6.84 (br t, 1 H, NH), 7.08-7.29 (m, 10H), 7.40 (d,J=8.7 Hz, 2H), 8.03 (d, J=8.6 Hz, 2H); Anal. Calcd. for C₃₅H₃₉N₅O₆. 0.75CH₂Cl₂: C, 62.28; H, 5.92; N, 10.16. Found: C, 62.23; H, 5.76; N, 10.12.

EXAMPLE 12

5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenyl-piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimid-ine.

a.

1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-(4-nitro-phenyl)pyrimidine.

A mixture of methyl 2-{(4-nitrophen-yl)methylene}-3-oxobutyrate (12.46g, 0.05 mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), andNaOAc (9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at 70-75°C. for 4 hours. The mixture was cooled and poured into ice-water (300mL). The precipitate formed was filtered, washed with water, and dried.The crude product was purified by flash column chromatography on silicagel using 10% through 30% EtOAc in hexane as the gradient eluent (9.8 g,64%). The ¹H-NMR analysis of the product showed it to be a 19:1 mixtureof the amine/imine tautomers which was used as such in the next step.¹H-NMR (CDCl₃): δ 2.32, 2.38 (2 s, 3H), 3.59, 3.70 (2 s, 3H), 3.70, 3.85(2 s, 3H), 5.40, 5.66 (s, d, J=3 Hz, 1H), 5.50, 6.08 (s, d, J=3 Hz, 1H),7.43, 7.45 (2 d, J=9 Hz, 2H), 8.10, 8.11 (2 d, J=9 Hz, 2H).

b.1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred mixture of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)pyrimidine(5.7 g, 0.0187 mol), NaHCO₃ (6.27 g, 0.074 mol), CH₂Cl₂ (200 mL), andwater (50 mL) at 0-5° C., 4-nitrophenyl chloroformate (3.76 g, 0.0186mol) was added in 5 min and the mixture was allowed to warm to roomtemperature. After 10 hours, the TLC analysis of the reaction mixtureshowed the presence of a small amount of starting pyrimidine, therefore,more 4-nitrophenyl chloroformate (0.65 g, 0.0032 mol) was added and thestirring continued for an additional 4 hours. The two layers wereseparated, the CH₂Cl₂ layer was washed with saturated aqueous NaHCO₃solution (3×50 mL), dried (MgSO₄), and the solvent evaporated. Theresidue was recrystallized from CH₂Cl₂ and hexane to give the product aswhite crystals (12.8 g, 89%); ¹H-NMR (CDCl₃): δ 2.48 (s, 3H), 3.69 (s,3H), 3.94 (s, 3H), 6.34 (s, 1H), 7.36 (d, J=9.1 Hz, 2H), 7.46 (d, J=8.7Hz, 2H), 8.14 (d, J=8.7 Hz, 2H), 8.26 (d, J=9.1 Hz, 2H); m.p. 168-169°C. Anal. Calcd. for C₂₁H₁₈N₄O₉: C, 53.62; H, 3.86; N, 11.91. Found: C,53.69; H, 3.92; N, 11.85.

c.5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-di-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydro-pyrimidine.

To a stirred solution of1,6-dihydro-2-methoxy-6-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}carboxamidopyrimi dine (0.208 g, 0.33 mmol) in THF (10 mL) at 5° C.under argon, 3 N HCl (6 mL) was added and the mixture was allowed towarm to room temperature. After 2 hours, solvents were evaporatedcompletely, the residue was treated with 40 mL of 10% NaHCO₃, theproduct was extracted with CH₂Cl₂ (2×15 mL) and the combined extractswere dried (MgSO₄). Solvent was evaporated and the residue wascrystallized from hexane and EtOAc (0.20 g, 97%); m.p. 197-198° C.;¹H-NMR (CDCl₃): δ 1.63-1.67 (m, 2H), 2.23-2.28 (m, 2H), 2.34 (s, 3H),2.37-2.42 (m, 8H), 3.20-3.41 (m, 2H), 3.69 (s, 3H), 6.75 (s, 1H),7.08-7.26 (m, 11H), 7.46 (d, J=8.7 Hz, 2 H), 8.08 (d, J=8.7 Hz, 2H),8.77 (br t, 1 H, NH); Anal. Calcd. for C₃₄H₃₇N₅O₆: C, 66.76; H, 6.10; N,11.45. Found: C, 66.48; H, 5.97; N, 11.25.

EXAMPLE 13

1-{N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl)propyl}]carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.

To a stirred mixture of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g, 1 mmol) and K₂CO₃(0.552 g, 4 mmol) in anhydrous THF (10 mL) at room temperature underargon atmosphere, a solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propyl-amine (0.390 g, 1.2 mmol, 1.2 eq) in THF (10 mL)was added and the stirring was continued 6 for 2 hours. The solid wasremoved by filtration and the solution was cooled to 0-5° C. 6N HCl (2mL) was added to the solution and stirring was continued. After 3 hours,solvents were evaporated completely, the residue was redissolved inCH₂Cl₂ (20 mL), washed with 10% NaHCO₃ (2×10 mL), and dried (MgSO₄).Solvent was evaporated and the residue was purified by columnchromatography using 1:1 hexane/EtOAc to 1000 EtOAc as gradient eluent.The oily product was crystallized from hexane and EtOAc (0.55 g, 86%);m.p. 100-102° C.; ¹H-NMR (CDCl₃): δ 1.65-1.80 (m, 2H), 2.26-2.31 (m, 2H), 2.35 (s, 3H), 2.39-2.44 (m, 6H), 3.18-3.40 (m, 2 H), 3.69 (s, 3H),3.73 (s, 3H), 6.75 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 6.84 (br s, 1 H,NH), 7.10 (d, J=8.7 Hz, 2H), 7.18-7.26 (m, 5H), 7.46 (d, J=8.6 Hz, 2H),8.08 (d, J=8.6 Hz, 2H), 8.78 (br t, 1 H, NH); Anal. Calcd. forC₃₅H₃₉N₅O₇. 0.12 CH₂Cl₂.0.12 EtOAc: C, 64.54; H, 6.12; N, 10.57. Found:C, 64.44; H, 6.12; N, 10.28.

EXAMPLE 14

1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine(Scheme 2).

To a stirred mixture of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(0.47 g, 1 mmol), K₂CO₃ (0.276 g, 2 mmol) in anhydrous THF (10 mL) atroom temperature under argon atmosphere, a solution of3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.332 g, 1.2mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continuedfor 2 hours. The solid was removed by filtration and the solution wascooled to 0-5° C. To this, 6 N HCl (2 mL) was added and the stirringcontinued. After 3 hours, solvents were evaporated completely, theresidue was redissolved in CH₂Cl₂ (20 mL), washed with 10% NaHCO₃ (2×10mL), and dried (MgSO₄). Solvent was evaporated and the residue waspurified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAcas gradient eluent. The oily product was crystallized from hexane andEtOAc (0.55 g, 86%); m.p. 180-181° C.; ¹H-NMR (CDCl₃): δ 1.60-1.80 (m,2H), 1.85-1.95 (m, 2H), 2.03-2.10 (m, 2H), 2.28-2.33 (m, 2H), 2.35 (s,3H), 2.48-2.50 (m, 2H), 3.20-3.40 (m, 2H), 3.60 (s, 3H), 3.68 (s, 3H),6.75 (s, 1H), 7.20-7.34 (m, 6H), 7.46 (d, J=8.8 Hz, 2 H), 8.07 (d, J=8.8Hz, 2H), 8.78 (br t, 1 H, NH); Anal. Calcd. for C₃₀H₃₅N₅O₈: C, 60.70; H,5.94; N, 11.80. Found: C, 60.71; H, 5.99; N, 11.43.

EXAMPLES 14a & 14b

(+)-1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidineand (−)-1-{N-[3-(4-Methoxycarbonyl-4-phenyl-piperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine(Scheme 3).

a.(−)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitro-phenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine and(+)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine.

To a stirred solution of(±)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (2.66 g, 5.6 mmol) in anhydrous THF (80mL) at room temperature under argon atmosphere, a solution of(S)-(−)-α-methylbenzylamine (0.82 g, 6.78 mmol, 1.2 eq) in THF (5 mL)was added and the stirring was continued for 6 hours. Solvent wasevaporated from the reaction mixture, the residue was redissolved inCH₂Cl₂ (50 mL), washed with 5% NaHCO₃ (3'25 mL), brine (50 mL), anddried (MgSO₄). Solvent was evaporated and the residue was purified byflash chromatography on silica gel using 5% to 30% EtOAc in hexane asthe gradient eluent. The first major product to elute was(−)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine and this compound was crystallized fromisopropyl ether (0.85 g, 33.6%); m.p. 119-120° C.; [α]_(D)=−329.32(CH₂Cl₂, 10.3 g/100 mL); ¹H-NMR (CDCl₃): δ 1.47 (d, J=7 Hz, 3H), 2.40(s, 3H), 3.61 (s, 3H), 3.95 (s, 3H), 4.96 (quint, J=6.5 Hz, 2H), 6.66(s, 1H), 6.82 (d, J=6.8 Hz, 1H, NH), 7.22-7.36 (m, 5H), 7.43 (d, J=8.6Hz, 2H), 8.09 (d, J=8.6 Hz, 2H); Anal. Calcd. for C₂₃H₂₄N₄O₆: C, 61.06;H, 5.35; N, 12.38. Found: C, 60.85; H, 5.13; N, 12.42. The second majorcompound to elute was(+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine and this compound was crystallized from isopropyl ether (0.92g, 36.4%); m.p. 138-140° C.; [α]_(D)=+171.81 (CH₂Cl₂₁ 11.31 g/100 mL);¹H-NMR (CDCl₃): δ 1.47 (d, J=7 Hz, 3H), 2.42 (s, 3H), 3.644 (s, 3H),3.917 (s, 3H), 4.989 (quint, J=6.5 Hz, 2H), 6.70 (s, 1H), 6.81 (d, J=6.8Hz, 1 H, NH), 7.22-7.35 (m, 5H), 7.36 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6Hz, 2H); Anal. Calcd. for C₂₃H₂₄N₄O₆: C, 61.06; H, 5.35; N, 12.38.Found: C, 60.95; H, 5.20; N, 12.38.

b. (+)-1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.

A solution of (+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine (0.226 g, 0.5 mmol) and1,8-diazabicyclo[5.4.0]-unde-7-ene (DBU) (0.076 g, 0.5 mmol) in CH₂Cl₂(10 mL) was stirred and refluxed for 4 hours and the solvent evaporated.The product was purified by column chromatography using 30% EtOAc inhexane as the eluent. The product was found to be a mixture of theamine-imine tautomers (0.120 g, 78.7%); [α]_(D)=+14.5 (CH₂Cl₂, 6 g/100mL)

To a well-stirred solution of (+)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine (0.12 g, 0.393mmol) and pyridine (0.5 mL) in CH₂Cl₂ (10 In- mL) at 0-5° C.,4-nitrophenyl chloroformate (0.095 g, 0.472 mmol) was added in 5 min andthe mixture was allowed to warm to room temperature. After 2 h,saturated aqueous NaHCO₃ solution (10 mL) was added and the stirringcontinued for 30 min. The two layers were separated, the CH₂Cl₂ layerwas washed with saturated aqueous NaHCO₃ solution (3×5 mL), dried(Na₂SO₄), and the solvent evaporated. The residue was redissolved in THF(10 mL) and mixed with K₂CO₃ (0.11 g, 0.8 mmol). To this, a solution of3-[4-methoxycarbonyl-4-phenyl piperidin-1-yl]propylamine (0.138 g, 0.5mmol) in THF (5 mL) was added and the mixture was stirred for 2 hours.The solid was removed by filtration and the solution was cooled to 0-5°C. To this, 6 N HCl (0.5 mL) was added and the stirring continued. After3 hours, solvents were evaporated completely, the residue wasredissolved in CH₂Cl₂ (20 mL), washed with 10% NaHCO₃ (4×5 mL), anddried (MgSO₄). Solvent was evaporated and the residue was purified bycolumn chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradienteluent. The oily product was crystallized from hexane and EtOAc (0.19 g,82%); m.p. 138-140° C.; [α]_(D)=+108 (CH₂Cl₂, 6.65 g/100 mL); ¹H-NMR(CDCl₃): 1.60-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2.03-2.10 (m, 2H),2.28-2.33 (m, 2H), 2.35 (s, 3H), 2.48-2.50 (m, 2H), 3.20-3.40 (m, 2H),3.60 (s, 3H), 3.68 (s, 3H), 6.75 (s, 1H), 7.20-7.34 (m, 5H), 7.46 (d,J=8.8 Hz, 2H), 7.60 (br s, 1 H, N H), 8.07 (d, J=8.8 Hz, 2H), 8.-78 (brt, 1 H, NH); Anal. Calcd. for C₃₀H₃₅N₅O₈. 0.2 CH₂Cl₂. 0.2 EtOAc: C,59.27; H, 5.94; N, 11.15. Found: C, 59.07; H, 5.76; N, 10.99.

c. (−)-1-{N-[3-(4-Methoxycarbonyl-4-phenyl piperidin-1-yl)propyl})carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.

A solution of (−)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine (0.35 g, 0.774 mmol) and1,8-diazabicyclo[5.4.0]-unde-7-ene (DBU) (0.117 g, 0.774 mmol) in CH₂Cl₂(10 mL) was stirred and refluxed for 8 hours and the solvent evaporated.The product was purified by column chromatography using 30% EtOAc inhexane as the eluent. The product,(−)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine,was found to be a mixture of the amine-imine tautomers (0.170 g, 72%).To a well-stirred solution of (−)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine (0.152 g, 0.5mmol) and pyridine (0.5 mL) in CH₂Cl₂ (10 mL) at 0-5° C., 4-nitrophenylchloroformate (0.121 g, 0.6 mmol) was added in 5 min and the mixture wasallowed to warm to room temperature. After 2 hours, saturated aqueousNaHCO₃ solution (10 mL) was added and the stirring continued for 30 min.The two layers were separated, the CH₂Cl₂ layer was washed withsaturated aqueous NaHCO₃ solution (3×5 mL), dried (Na₂SO₄), and thesolvent evaporated. The residue was redissolved in THF (10 mL) and mixedwith K₂CO₃ (0.165 g, 1.2 mmol). To this, a solution of3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.166 g, 0.6mmol) in THF (5 mL) was added and the mixture was stirred for 2 hours.The solid was removed by filtration and the solution was cooled to 0-5°C. To this, 6 N HCl (0.5 mL) was added and the stirring continued. After3 hours, solvents were evaporated completely, the residue wasredissolved in CH₂Cl₂ (20 mL), washed with 10% NaHCO₃ (4×5 mL), anddried (MgSO₄). Solvent was evaporated and the residue was purified bycolumn chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradienteluent. The oily product was crystallized from hexane and EtOAc (0.19 g,64%); m.p. 138-140° C.; [α]_(D)=−106 (CH₂Cl₂, 3.95 g/100 mL); ¹H-NMR(CDCl₃): δ 1.60-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2.03-2.10 (m, 2H),2.28-2.33 (m, 2H), 2.35 (s, 3H), 2.48-2.50 (m, 2H), 3.20-3.40 (m, 2H),3.60 (s, 3H), 3.68 (s, 3H), 6.75 (s, 1H), 7.20-7.34 (m, 6H), 7.46 (d,J=8.8 Hz, 2H), 8.07 (d, J=8.8 Hz, 2H), 8.78 (br t, 1 H, NH); Anal.Calcd. for C₃₀H₃₅N₅O₈. 0.4 CH₂Cl₂: C, 58.18; H, 5.75; N, 11.16. Found:C, 58.25; H, 5.67; N, 10.98.

EXAMPLE 15

1-{N-[3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.

To a stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.235 g, 0.5 mmol), K₂CO₃ (0.138 g, 1 mmol) inanhydrous THF (10 mL) at room temperature under argon atmosphere, asolution of 3-[4-ethoxycarbonyl-4-phenylpiperidin-1-yl]propylamine(0.174 g, 0.6 mmol, 1.2 eq) in THF (5 mL) was added and the stirring wascontinued for 4.5 h. The solid was removed by filtration and thesolution was cooled to 0-5° C. To this, 6 N HCl (0.5 mL) was added andthe stirring continued. After 1 hour, solvents were evaporatedcompletely, the residue was redissolved in CH₂Cl₂ (20 mL), washed with 1N NaHCO₃ (2×10 mL), and dried (MgSO₄). Solvent was evaporated and theresidue was purified by column chromatography using 1:1 hexane/EtOAc to100% EtOAc as gradient eluent. The oily product was crystallized fromhexane and EtOAc (0.182 g, 60%); m.p. 79-80° C.; ¹H-NMR (CDCl₃): δ 1.13(t, J=7 Hz, 3H), 1.62-1.78 (m, 2H), 1.87-2.0 (m, 2H), 2.06-2.18 (m, 2H),2.2-2.31 (m, 2H), 2.37(s, 3H), 2.50-2.55 (m, 2H), 2.72-2.80 (m, 2H),3.25-3.40 (m, 2H), 3.68 (s, 3H), 4.07 (q, J=7 Hz, 2H), 6.75 (s, 1H),7.18-7.36 (m, 6H), 7.48 (d, J 8.7 Hz, 2H), 8.11 (d, J=8.7 Hz, 2H), 8.79(br t, 1 H, NH); Anal. Calcd. for C₃₁H₃₇N₅O₈. 0.5 C₆H₁₂. 1.25 H₂O: C,62.71; H, 7.06; N, 11.55. Found: C, 62.90; H, 7.20; N, 11.33.

EXAMPLE 16

5-Benzyloxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetrahydro pyrimidine.

a. Benzyl 2-{(3,4-methylenedioxyphenyl)methylene}-3-oxobutyrate.

A mixture of 3,4-methylenedioxybenzaldehyde (15.013 g, 0.1 mol), benzylacetoacetate (20.18 g, 0.105 mol), piperidine (0.41 g, 476 mL, 4.8mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (500mL) was stirred at room temperature for 48 hours. The white solid,benzyl 2-{(3,4-methylenedioxyphenyl)methylene}-3-oxobutyrate, formed wasfiltered, washed with 2-propanol (2×50 mL) and dried (29.84 g, 92%);m.p. a , 137-138° C.

b.5-Benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-methylenedioxyphenyl)pyrimidine.A mixture of benzyl2-{(3,4-methylenedioxyphenyl)methylene}-3-oxobutyrate (16.266 g, 0.05mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), and NaHCO₃(8.4 g, 0.1 mol) in EtOH (400 mL) was stirred and heated at 85-90° C.for 48 h. The solid was removed by filtration and ethanol was evaporatedfrom the filtrate. The residue was redissolved in EtOAc (300 mL), washedwith water (2×100 mL), dried (Na₂SO₄), and the solvent evaporated. Thecrude product was purified by flash column chromatography on silica gelusing 10% through 30% EtOAc in hexane as the gradient eluent, to leavethe product as a viscous oil (11.8 g, 62%). The ¹H-NMR analysis of theproduct showed it to be a 1:1 mixture of the amine/imine tautomers andwas used as such in the next step.

c.5-Benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-methylenedioxyphenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred solution of5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-methylenedioxyphenyl)pyrimidine (10.0 g, 0.0263) and pyridine (5 mL) in CH₂Cl₂ (500 mL) at0-5° C., 4-nitrophenyl chloroformate (7.56 g, 0.038 mol) was added in 5min and the mixture was allowed to warm to room temperature. After 16hours, saturated aqueous NaHCO₃ solution (100 mL) was added and thestirring continued for 30 min. The two layers were separated, the CH₂Cl₂layer was washed with saturated aqueous NaHCO₃ solution (3×50 mL), dried(Na₂SO₄), and the solvent evaporated. The residue on trituration withisopropyl ether gave the product as white crystals (12.8 g, 89%); m.p.146-147° C.; ¹H-NMR (CDCl₃): δ 2.46 (s, 3H), 3.93 (s, 3H), 5.19, 5.92(AB q, J=12.6 Hz, 2H), 5. 92 (s, 2H), 6.22 (s, 1H), 6.68-6.78 (m, 3H),7.15-7.29 (m, 5H), 7.30 (d, J=9.1 Hz, 2H), 8.22 (d, J=9.1 Hz, 2H); Anal.Calcd. for C₂₈H₂₃N₃O₉. 0.25 H₂O. 0.25 CH₂Cl₂: C, 59.40; H, 4.23; N,7.36. Found: C, 59.42; H, 4.07; N, 7.30.

d.5-Benzyloxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetrahydro pyrimidine.

To a stirred mixture of 5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-methylenedioxyphenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(1.091 g, 2 mmol), K₂CO₃ (0.552 g, 4 mmol) in anhydrous THF (20 mL) atroom temperature under argon atmosphere, a solution of3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.663 g, 2.4mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continuedfor 2 hours. The solid was removed by filtration and the solution wascooled to 0-5° C. To this, 6 N HCl (2 mL) was added and the stirringcontinued. After 3 hours, the solvent was evaporated completely, theresidue was redissolved in CH₂Cl₂ (20 mL), washed with 10% NaHCO₃ (2×10mL), and dried (MgSO₄). Solvent was evaporated and the residue waspurified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAcas gradient eluent, to afford the pure product as a white foam (0.55 g,86%); m.p. 100-102° C.; ¹H-NMR (CDCl₃):5 1.64-1.80 (m, 2H), 1.80-1.99(m, 2H), 2.0-2.09 (m, 2H), 2.24-2.29 (m, 2 H), 2.33 (s, 3H), 2.48-2.50(m, 2H), 2.76-2.83 (m, 2 H), 3.21-3.37 (m, 2H), 3.60 (s, 3H), 5.02, 5.18(AB q, J=12.5 Hz, 2H), 5.88 (s, 2H), 6.61-6.78 (m, 3 H), 6.80 (s, 1H),7.14-7.39 (m, 11H), 8.75 (br t, 1 H, NH); Anal. Calcd. for C₃₇H₄₀N₄O₈.0.3 H₂O: C, 65.92; H, 6.07; N, 8.31. Found: C, 65.95; H, 6.00; N, 8.18.

EXAMPLE 17

5-Methoxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetra hydropyrimidine.

To a stirred solution of5-benzyloxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine (0.320 g, 0.48 mmol) in methanol (20 mL)and HCOOH (1 mL) at 0-5° C., 10% Pd—C (0.26 g) was added in portions andthe cooling bath was removed. TLC analysis of the reaction mixture atfrequent intervals showed the completion of the reaction after 2 hours.The catalyst was removed by filtration and the solvent was evaporated toleave 1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylic acid as a whitesolid (0.275 g, 99%). The product was used in the next step without anyfurther purification and characterization. A mixture of1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylic acid (0.2 g,0.346 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimidehydrochloride (0.382 g, 2 mmol), and 4-(N,N-dimethylamino)pyridine(0.488 g, 4 mmol), in methanol (20 mL) was stirred and refluxed for 5 hand the solvent evaporated. The residue was redissolved in CH₂Cl₂ (15mL), washed with saturated aqueous ammonium chloride solution (3×10 mL),and dried (Na₂SO₄). Evaporation of the solvent left the pure product aswhite powder (0.202 g, 99%); m.p. 139-141° C.; ¹H-NMR (CDCl₃): δ1.62-1.80 (m, 2H), 1.95-2.20 (m, 4H), 2.35 (s, 3H), 2.30-2.55 (m, 4H),2.76-2.90 (m, 2H), 3.21-3.40 (m, 2H), 3.61 (s, 3H), 3.67 (s, 3H), 5.89(s, 2H), 6.61-6.82 (m, 3H), 6.63 (s, 1H), 7.21-7.35 (m, 6H), 8.79 (br t,1 H, NH); Anal. Calcd. for C₃₁H₃₆N₄O₈. 0.3 EtOAc: C, 62.47; H, 6.25; N,9.05. Found: C, 62.64; H, 6.25; N, 8.87.

EXAMPLE 18

5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-methoxy-6-(4-nitrophenyl)pyrimidine.

a. 2-Cyanoethyl 3-{(4-nitrophenyl)methylene}-4 oxopentanoate. A mixtureof ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile(18.48 g, 0.26 mol) was stirred and heated at 200-205° C. for 2 hoursand the ethanol formed was removed by distillation. The residue wassubjected to high vacuum distillation and the fraction distilling at120-125° C. at 0.4 mm Hg was collected to get 2-cyanoethylpropionylacetate (21.5 g, 73.4%). A mixture of 4-nitrobenzaldehyde(14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g,274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperaturefor 24 h. The white solid, 2-cyanoethyl3-{(4-nitrophenyl)methylene}-4-oxopentanoate, was filtered, washed with2-propanol (2×50 mL) dried and used without further purification (Yield:28.34 g, 97%); m.p. 98-100° C.

b.5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.

A mixture of 2-cyanoethyl 3-{(4-nitrophenyl) methylene}-4-oxopentanoate(5.00 g, 16.54 mmol), O-methylisourea hydrogen sulfate (3.422 g, 19.85mmol), and NaHCO₃ (2.78 g, 33.08 mol) in EtOH (70 mL) was stirred andheated at 85-90° C. for 5 hours. The solid was removed by filtration andethanol was evaporated from the filtrate. The residue was redissolved inEtOAc (300 mL), washed with water (2×100 mL), dried (Na₂SO₄), and thesolvent evaporated. The crude product was purified by flash columnchromatography on silica gel using CHCl/methanol (30:1) as the eluent,to leave the product as a white solid (2.95 g, 50%). The ¹H-NMR analysisof the product showed it to be a 5:1 mixture of the amine/iminetautomers and was used as such in the next step.

c.5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred solution of 5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)pyrimidine(2.64 g, 7.36 mmol) and pyridine (1.19 mL, 14.72 mmol) in CH₂Cl₂ (100mL) at 0-5° C., 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) wasadded in 5 min and the mixture was allowed to warm to room temperature.After 16 h, saturated aqueous NaHCO₃ solution (25 mL) was added and thestirring continued for 30 min. The two layers were separated, the CH₂Cl₂layer was washed with saturated aqueous NaHCO₃ solution (3×50 mL), dried(Na₂SO₄), and the solvent evaporated. The crude product was purified byflash column chromatography on silica gel using CHCl₃/EtOAc (25:1) asthe eluent to give the product as a viscous oil (1.70 g, 44%); ¹H-NMR(CDCl₃): δ 1.24 (t, J=7 Hz, 3H), 2.61-2.68 (m, 2H), 2.88-2.92 (m, 2H),3.97 (s, 3H), 4.32 (t, J=7 Hz, 2H), 6.34 (s, 1H), 7.37 (d, J=9.2 Hz,2H), 7.50 (d, J=8.7 Hz, 2H), 8.18 (d, J=8.7 Hz, 2H), 8.28 (d, J=9.2 Hz,2H).

d.5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-methoxy-6-(4-nitrophenyl) pyrimidine.

To a stirred mixture of5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl)pyrimidine (0.940 g, 2 mmol) and K₂CO₃(0.552 g, 4 mmol) in anhydrous THP (20 mL) at room temperature underargon atmosphere, a solution of 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.882 g, 3 mmol, 1.5 eq) in THF (5 mL) wasadded and the stirring was continued for 1 h. Solvent was evaporatedfrom the reaction mixture, the residue was redissolved in CH₂Cl₂ (50mL), washed with 5% NaHCO₃ (3×25 mL), brine (50 mL), and dried (MgSO₄).Solvent was evaporated and the residue was purified by flashchromatography on silica gel using 10% methanol in EtOAc as the eluentto give the desired product as an oil, which on trituration with hexaneand drops of EtOAc became a white powder (1.71 g, 80%); m.p. 62-63° C.;¹H-NMR (CDCl₃):6 1.16 (t, J=7.5 Hz, 3 H), 1.62-1.78 (m, 2H), 1.80-1.84(m, 2H), 2.06-2.18 (m, 2H), 2.28-2.36 (m, 2H), 2.50-2.53 (m, 4H),2.58-2.63 (m, 2H), 2.70-2.84 (m, 4H), 3.25-3.40 (m, 2H), 3.61 (8, 3H),3.92 (s, 3H), 4.26 (m, 2H), 6.66 (s, 1H), 6.82 (br t, 1 H, NH),7.22-7.33 (m, 6H), 7.43 (d, J=7.8 Hz, 2H), 8.10 (d, J=7.8 Hz, 2H); Anal.Calcd. for C₃₄H₄₀N₆O₈. 0.1 C₆H₁₂. 0.5 H₂O: C, 61.44; H, 6.27; N, 12.93.Found: C, 61.44; H, 6.27; N, 12.11.

EXAMPLE 19

(+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 4).

a. 2-Cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate.

A mixture of ethyl propionylacetate (25 g, 0.173 mol) and3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at200-205° C. for 2 h and the ethanol formed was removed by distillation.The residue was subjected to high vacuum distillation and the fractiondistilling at 120-125° C. at 0.4 mm of Hg was collected to get2-cyanoethyl propionylacetate (21.5 g, 73.4%).

A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethylpropionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400mL) was stirred at room temperature for 24 h. The white solid,2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxo pentanoate, formed wasfiltered, washed with 2-propanol (2×50 mL) and dried (28.34 g, 97%);m.p. 98-100° C.

b.5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.

A mixture of 2-cyanoethyl 3-{(4-nitrophenyl)methylene} -4-oxopentanoate(5.00 g, 16.54 mmol), O-methylisourea hydrogen sulfate (3.422 g, 19.85mmol), and NaHCO: (2.78 g, 33.08 mol) in EtOH (70 mL) was stirred andheated at 85-90° C. for 5 h. The solid was removed by filtration andethanol was evaporated from the filtrate. The residue was redissolved inEtOAc (300 mL), washed with water (2×100 mL), dried (Na₂SO₄), and thesolvent evaporated. The crude product was purified by flash columnchromatography on silica gel using CHCl₃/methanol (30:1) as the eluent,to leave the product as a white solid (2.95 g, 50%). The ¹H-NMR analysisof the product showed it to be a 5:1 mixture of the amine/iminetautomers and was used as such in the next step.

c.5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred solution of 5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)pyrimidine(2.64 g, 7.36 mmol) and pyridine (1.19 mL, 14.72 mmol) in CH₂Cl₂ (100mL) at 0-5 ° C., 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) wasadded in 5 min and the mixture was allowed to warm to room temperature.After 16 h, saturated aqueous NaHCO₃ solution (25 mL) was added and thestirring continued for 30 min. The two layers were separated, the CH₂Cl₂layer was washed with saturated aqueous NaHCO₃ solution (3×50 mL), dried(Na₂SO₄), and the solvent evaporated. The crude product was purified byflash column chromatography on silica gel using CHCl₃/EtOAc (25:1) asthe eluent to give the product as a viscous oil (1.70 g, 44%); ¹H-NMR(CDCl₃): δ 1.24 (t, J=7 Hz, 3H), 2.61-2.68 (m, 2H), 2.88-2.92 (m, 2H),3.97 (s, 3H), 4.32 (t, J=7 Hz, 2H), 6.34 (s, 1H), 7.37 (d, J=9.2 Hz,2H), 7.50 (d, J=8.7 Hz, 2H), 8.18 (d, J=8.7 Hz, 2H), 8.28 (d, J=9.2 Hz,2H).

d.5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine.

To a stirred solution of5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(17.5 g, 33.43 mmol) in anhydrous THF (200 mL) at room temperature underargon atmosphere, (R)-(+)-a-methylbenzylamine (4.86 g, 40.11 mmol) wasadded and the stirring was continued for 16 h. Solvent was evaporatedfrom the reaction mixture and the residue was purified by flashchromatography on silica gel using toluene/EtOAc (20:3) as the eluent.The first major product to elute was(+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidineand obtained as a viscous oil (6.11 g, 36.2%); [α]_(D)=+299.5 (c=1.95,CHCl₃); ¹H-NMR (CDCl₃): δ 1.18 (t, J=7 Hz, 3H), 1.47 (d, J=7 Hz, 3H),2.61 (t, 2H), 2.7-2.92 (m, 2H), 3.98 (s, 3H), 4.20-4.32 (m, 2H), 4.96(quint, J=6.5 Hz, 2H), 6.66 (s, 1H), 6.82 (d, J=6.8 Hz, 1 H, NH),7.22-7.36 (m, 5H), 7.45 (d, J=8.6 Hz, 2H), 8.11 (d, J=8.6 Hz, 2H). Thesecond major compound to elute was(−)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidineand obtained as a viscous oil (5.92 g, 35%); [α]_(D)=−105.1 (c=3.9,CHCl₃); ¹H-NMR (CDCl₃): δ 1.20 (t, J=7 Hz, 3H), 1.48 (d, J=7 Hz, 3H),2.62 (t, 2H), 2.82 (q, 2H), 3.94 (s, 3H), 4.20-4.32 (m, 2H), 4.96(quint, J=6.5 Hz, 2H), 6.69 (s, 1H), 6.84 (d, J=6.8 Hz, 1 H, NH),7.22-7.36 (m, 5H), 7.39 (d, J=8.6 Hz, 2H), 8.06 (d, J=8.6 Hz, 2H).

e.(+)—S—(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.

To a stirred solution of(+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine (2.62 g, 5.182 mmol) in toluene (40 mL) was added1,8-diazabicyclo[5,4,0]-undec-7-ene (0.237,1.55 mmol) at roomtemperature and the resulting solution was heated at 90° C. for 3.5minutes. The solvent was evaporated and the residue was purified byflash column chromatography on silica gel using 9:1 CHCl₃/EtOAc as theeluent, to give 1.32 g (71%)of(+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine;[α]_(D)=+4.0 (c=3.25, CHCl₃).

f.(+)-5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well-stirred solution of 5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl) pyrimidine (1.62 g,4.52 mmol) and 4-(N,N-dimethylamino)pyridine (0.663 g, 5.43 mmol) inCH₂Cl₂ (50 mL) at 0-5° C., 4-nitrophenyl chloroformate (1.094 g, 5.43mmol) was added in 5 minutes and the mixture was allowed to warm to roomtemperature. After 3 hours the solvent evaporated and the product waspurified by flash column chromatography on silica gel using CHCl₃/EtOAc(25:1) as the eluent to give the product as a white solid (2.25 g, 95%);¹H-NMR (CDCl₃): δ 1.24 (t, J=7 Hz, 3H), 2.61-2.68 (m, 2H), 2.88-2.92 (m,2H), 3.97 (s, 3H), 4.32 (t, J=7 Hz, 2H), 6.34 (s, 1H), 7.37 (d, J=9.2Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 8.18 (d, J=8.7 Hz, 2H), 8.28 (d, J=9.2Hz, 2H); [α]_(D)=+317.2 (c=3.9, CHCl₃)

g.(+)-5-(2-Cyanoethoxycarbonyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine.

To a stirred mixture of (+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (3.60 g, 6.878 mmol) inanhydrous THF (100 mL) at room temperature under argon atmosphere, asolution of 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine(2.47 g, 8.94 mmol, 1.3 eq) in THF (10 mL) was added and the stirringwas continued for 12 hours. The mixture was cooled to 0° C. and aqueous6N hydrochloric acid (10 mL). The mixture was allowed to warm to roomtemperature and the stirring was continued for 5 h. Solvent wasevaporated from the reaction mixture, the residue was purified by flashchromatography on silica gel using ethyl acetate (800 mL) followed bychloroform-methanol-2M ammonia in methanol (90/8/4) as the eluent, toobtain the desired product as a white powder (4.40 g, 98.56 );¹H-NMR(CDCl₃): δ 1.23 (t, J=7.5 Hz, 3H), 2.0-2.1 (m, 2H), 2.40-2.95 (m, 12H),3.25-3.50 (m, 4H), 3.65 (s, 3H), 4.27-4.32 (m, 2H), 6.64 (s, 1H),7.20-7.33 (m, 5H), 7.49 (d, J=7.8 Hz, 2H), 8.08 (d, J=7.8 Hz, 2H),8.70-8.90 (m, 2H); [α]_(D)=+112.1 (c=2.15, CHCl₃); This product was usedin the next step without any additional analysis.

h.(+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine.

To a stirred solution of5-(2-cyanoethoxycarbonyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine(4.40 g, 6.8 mmol) in acetone (50 mL) at 0° C., sodium hydroxidesolution (1 N, 27.2 mL, 4 eq.) was added drop wise and the stirring wascontinued until the disappearance of the starting material (1 hour).Most of the acetone from the mixture was evaporated under reducedpressure while 20 keeping the temperature at 0° C. and the residue wasadjusted to pH 7.0 by the addition of 1N hydrochloric acid. The whiteprecipitate of(+)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine-5-carboxylic acid formed was filtered and dried under vacuum(3.59 g, 89%). ¹H-NMR (CDCl₃): δ 1.07 (t, J=7.5 Hz, 3H), 1.55-1.70 (m,2H), 1.72-1.84 (m, 2H), 1.84-2.15 (m, 2H), 2.20-2.40 (m, 4H), 2.70-2.90(m, 2H), 3.10-3.40 (m, 4H), 3.51 (s, 3H), 6.54 (s, 1H), 7.18-7.38 (m,6H), 7.41 (d, J=7.8 Hz, 2H), 8.15 (d, J=7.8 Hz, 2H), 8.79 (br t, 1 H, NH), 10.05 (br S, 1 H, COOH); This product was used in the next stepwithout any additional analysis.

A mixture of(+)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine-5-carboxylic acid (0.350 g,0.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.2264 g, 1.181 mmol, 2eq.), and 4-(N,N-dimethylamino)pyridine (0.1443g, 1.181 mmol, 2 eq) in anhydrous dichloromethane was stirred at roomtemperature for 2 h. To this, 40% aqueous ammonia (0.6 mL) was added andthe stirring was continued for 12 h. The mixture was diluted with 100 mLof dichloromethane and washed with saturated aqueous ammonium chloridesolution (3×20 mL). Solvent was evaporated from the dried (magnesiumsulfate) dichloromethane solution and the residue was purified by columnchromatography on silica gel using chloroform-methanol-2M ammonia inmethanol (500/16/8) as the eluent, to obtain the desired product as awhite powder (0.24 g, 69%); m.p. 107-109° C.; ¹H-NMR (CDCl₃): δ 1.20 (t,J=7.5 Hz, 3H), 1.66-1.72 (m, 2H), 1.79-2.00 (m, 3H), 2.00-2.20 (m, 2H),2.29-2.35 (m, 2H), 2.42-2.60 (m, 2H), 2.62-2.82 (m, 3H), 3.20-3.40 (m,2H), 3.60 (s, 3H), 5.70 (br m, 2 H, NH ₂), 6.59 (s, 1 H), 7.20-7.39 (m,6H), 7.52 (d, J=7.8 Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 8.82 (t, 1H);[α]_(D)=+115.71 (c=1.4, CHCl₃); Anal. Calcd. for C₃₀H₃₆N₆O₇. 0.8 H₂O: C,59.36; H, 6.24; N, 13.84. Found: C, 59.47; H, 6.07; N, 13.64.

EXAMPLE 20

(+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 5).

a. Benzyl 3-[(3,4-difluorophenyl)methylene]-4-oxopentanoate. A solutionof benzyl propionylacetate (36.3 g, 176 mmol), 3,4-difluorobenzaldehyde(25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49mL, 9.0 mmol) were refluxed with removal of water using Dean-Starkapparatus for 5 h. The solvent was removed in vacuo and the residue wasdissolved in EtOAc. It was washed with water (100 mL) followed by brine(100 mL) and dried over anhydrous Na₂SO₄. Solvent was evaporated to getpale yellow syrup (60.2 g). It was used in the next step without furtherpurification.

b.5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine.A suspension of benzyl 3-[(3,4-difluorophenyl)methylene]-4-oxopentanoate(16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02mmol), NaHCO₃ (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70° C.for 20 h. After cooling to room temperature, the mixture was filteredand the filtrate was diluted with EtOAc (300 mL) and then washed withwater (4×100 mL), brine (200 mL) and dried over Na₂SO₄. After removal ofsolvent, the residue was purified by column chromatography (SiO₂,EtOAc/Hexane, 10%-30%) to get5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-difluorophenyl)pyrimidineas a colorless oil (10.6 g, 58%). The NMR analysis showed it to be amixture of amine/imine tautomers and was used as is in the next step.

c.5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)—1-[(4-nitrophenyloxy)carbonyl]pyrimidine.To a well stirred solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethyl aminopyridine(6.99 g, 57.25 mmol) in CH₂Cl₂ (200 mL) was added a powder of4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature.The reaction mixture was stirred for 12 hours and then the solvent wasremoved in vacuo. The residue was purified by chromatography (SiO2,EtOAc/Hexane 10-30%) to get5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidineas a colorless viscous oil(12.6 g, 50%).¹H NMR (CDCl₃): δ 1.24 (t, J=7.2Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (AB_(q), δ_(A)=5.08,δ_(B)=5.20, J=12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d,J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).

d.5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine. To a stirred mixture of5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (12.6 g, 22.86 mmol) in THF (150 mL) was added asolution of R-(+)-a-methyl benzylamine (3.53 mL, 27.44 mmol) at roomtemperature. The stirring was continued for 12 hours. Solvent wasremoved in vacuo. The yellow residue was dissolved in chloroform (200mL) and was washed with 10% K₂CO₃ solution (2×30 mL). The organic layerwas dried over Na₂SO₄₁ filtered and solvent was removed in vacuo. Theresulting mixture of diastereomers was separated by columnchromatography over silica gel with 9:1 Pet. ether:Ether to 4:1 Pet.ether:Ether. First major product to elute was5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine.Colorless oil, Rf=0.31(4:1 Pet ether:ether), wt.=3.8 g (60%),[α]_(D)=+267.05 (c=0.76, CHCl₃) ¹H NMR: δ 1.22 (t, J=7.5 Hz, 3H), 1.52(d, J=6.9 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3.99 (s, 3H), 4.99 (m, 1H),5.09 (AB_(q), δ_(A)=5.00, δ_(B)=5.19, J=12.6 Hz, 2H), 6.66 (s, 1H),6.99-7.36 (m, 13H).; Second major product to elute was(−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine.Colorless oil. Rf=0.22(4:1 Pet ether:ether), wt.=3.2 g (51.2%),[α]_(D)=−146.89 (c=0.38, CHCl₃), ¹H NMR: δ 1.22 (t, J=7.2 Hz, 3H), 1.49(d, J=6.6 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3.94 (s, 3H), 5.03 (m, 1H),5.11 (AB_(q), δ_(A)=5.02,δ_(B)=5.19, J=12.6 Hz, 2H), 6.68 (s, 1H),6.91-7.34 (m, 13H).

e.(+)-5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine.To a stirred solution of(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-(2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine (1.83 mmol,1.0 g) in toluene (10 mL) was added 1,8-diazabicyclo[5,4,0]-undec-7-ene(0.81 mmol,0.12 mL) at room temperature and the resulting solution washeated to reflux for 5 h and then stirred for 12 h at room temperature.The solvent was evaporated and the residue was purified by flash columnchromatography on silica gel with 3:1 EtOAc/Hexanes as the elutingsystem. 0.56 g of the(+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidinewas obtained (77%).

f.(+)-5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine. To a well stirred solution of(+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine(17.0 g, 44.04 mmol) and 4-dimethylaminopyridine (6.99 g, 57.25 mmol) inCH₂Cl₂ (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54g, 57.25 mmol) at room temperature. The reaction mixture was stirred for12 hours and then the solvent was removed in vacuo. The residue waspurified by chromatography (SiO2, EtOAc/Hexane 10-30%) to get(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a colorless viscous oil(19.3 g, 76%).

g.(+)-5-(Benzyloxycarbonyl)-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine. Toa stirred mixture of(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.55 g, 1.12 mmol) in THF (5 mL) was added asolution of 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine(0.31 g, 1.12 mmol) in THF (5 mL) at room temperature. The stirring wascontinued for 12 hours. A solution of 10% HCl in water (2 mL) was addedand stirred for 2 h. The solvent was then removed in vacuo and theresidue was extracted with ethyl acetate (3×10 mL). It was washed with10% aq. KOH solution, dried over Na₂SO₄ and solvent was removed in vacuoto obtain(+)-5-(benzyloxycarbonyl)-6-(3,4-difluorophenyl)-4-ethyl—{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidineas a white foamy compound (0.73 g, 96.6%) the purity of which wascharacterized as its HCl salt. It was used in the next step withoutfurther purification. Anal. Calcd. for C₃₇H₄₁ClF₂N₄O₆. 0.5CHCl₃:C,58.43; H, 5.43; N, 7.27. Found: C, 58.11, H; 5.85; N, 7.64.

h. 6-(3,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-5-carboxylicacid. To a suspension of 10% Pd—C (0.14 g, 20% by wt.) in MeOH (3 mL)was added the solution of(+)-5-(benzyloxycarbonyl)-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine at roomtemperature with constant stirring. A balloon filled with H₂ wasattached and the reaction mixture was stirred for 48 hours. The blacksuspension was filtered through a pad of celite and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, 10% MeOH in EtOAc) to obtain(+)-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-5-carboxylic acidas a white solid. M.P. 184-186° C.; [α]_(D)=+142.2 (c=0.25, CHCl₃) Thepurity was checked by combustion analysis as a HCl salt. Anal. Calcd.for C₃₀H₃₅ClF₂N₄O₆. 0.3CHCl₃:C, 55.40; H, 5.42; N, 8.53. Found: C,55.34; H; 5.80; N, 8.13.

i.(+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydro pyrimidine.

To a solution of(+)-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-5-carboxylic acid(0.22 g, 0.375 mmol) in CH₂Cl₂ (3 mL) was added 4-N,N-dimethylaminopyridine (0.14 g, 1.12 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g,1.12 mmol) under argon and the resulting solution was stirred at roomtemperature for 2h. Three drops of saturated NH₄OH was then added andthe solution was stirred for 48 h. The solution was washed with water (5ml) and dried over Na₂SO₄. The solvent was removed in vacuo and theresidue was purified by column chromatography (SiO₂, 10% MeOH in CHCl₃)to obtain 5-carboxamido-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidineas a beige solid (0.1 g, 45%). Characterized as HCl salt. M.P. 136-138°C., [α]_(D)=+111.44 (c=0.18, MeOH): δ 1.21 (t, J=7.5 Hz, 3H), 1.60-1.75(m, 2H), 1.92-2.1 (m, 8H), 2.33 (t, J=6.6 Hz, 2H), 2.44-2.52 (m, 2H),2.53-2.84 (m, 4H), 3.27-3.32 (m, 2H), 3.60 (s, 3H), 5.60 (br s,2H), 6.47(s, 1H), 7.05-7.33 (m, 8H), 8.80 (br t, 1H), Anal. Calcd. forC₃₀H₃₅ClF₂N₄O₆. 1.0 CHCl₃:C, 50.35; H. 5.04; N, 9.47. Found: C, 50.40;H; 5.33; N, 9.13.

EXAMPLE 21

6-(3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride (Scheme 7).

a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine. To a mixture ofN,N-bis-(2-chloroethyl)benzylamine (E.Szarvasi, Eur. J. Med. Chem. Chim.Ther. 11(2), 115-124, 1976) (60 g, 22 mmol), 2-pyridylacetonitrile (2.51ml, 22 mmol) and tetrabutylammonium hydrogen sulfate (0.26 g, 0.7 mmol)in toluene (10 ml), sodium hydroxide solution (2.43 g in 4.86 ml H₂O)was added over a 20 minute period. The reaction mixture was heated at 65° C. for 4 hours. The reaction mixture was cooled to room temperature,10 ml of water was added and the solution partitioned between ethylacetate (45 ml) and water. The organic layer was dried over sodiumsulfate, filtered and concentrated. Purification of the crude product bycolumn chromatography (hexane:EtOAc,2:3) gave 6.2 g (87%) of the titlecompound as a red solid; ¹H-NMR (CDCl₃): a 2.05 (d, J 13.1 Hz, 2H), 2.30(t, J=13.2 Hz, 2H), 2.48 (t, J=13.2 Hz, 2H), 2.97 (d, J=12.1 Hz, 2H),3.57 (s, 2H), 7.19-7.27 (m, 6H), 7.30 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 8.58 (d, J=4.6 Hz,1H).

b. 1-Benzyl-4-carboxamido-4-(2-pyridyl)piperidine. To1-benzyl-4-cyano-4-(2-pyridyl)piperidine (4.5 g, 14.3 mmol), 10 ml ofconc.H₂SO₄ was added and the solution was stirred at room temperaturefor 24 hours. It was cooled to 0° C., diluted with ice pieces and pouredinto crushed ice. The mixture was then carefully neutralized with 50%NaOH solution. The reaction mixture was repeatedly extracted withchloroform (3×25 ml), dried over sodium sulfate, filtered andconcentrated to give 4.5 g (95%)of the crude product which was used assuch for the subsequent step; ¹H-NMR (CDCl₃): δ 2.21-2.28 (m, 2H), 2.47(s, 6H), 3.41 (s, 2H), 5.23 (s, 1H), 6.40 (s, 1H), 7.12-7.29 (m, 6H),7.33 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 8.55 (d, J=4.6 Hz, 1H).

c. 1-Benzyl-4-(2-pyridyl)-piperidine. To1-benzyl-4-carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5 mmol) inanhydrous methanol (100 ml), HCl gas was bubbled through the solution at0° C. for 15 minutes. The reaction mixture was then refluxed for 24hours. It was cooled to room temperature, concentrated, neutralized with50% NaOH and repeatedly extracted with chloroform (3×25 ml). Thecombined organic layer was then dried over sodium sulfate, filtered andconcentrated. Flash chromatography (hexane:ethylacetate, 1:4) of thecrude product yielded 1.72 g (50%) of the product as a syrup; ¹H-NMR(CDCl₃) δ 1.8-1.94 (m, 4H), 2.11 (t, J=11.4 Hz, 2H), 2.70-2.72 (m,1H),3.02 (d, J=11.4 Hz, 2H), 3.54 (s, 2 H), 7.07-7.36 (m, 7H), 7.58 (t,J=7.6 Hz, 1H), 8.52 (d, J=4.6 Hz, 1H).

d. 3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme 6). To 1-Benzyl-4-(2-pyridyl)-piperidine (3. 2 6 g, 12.9 mmol) in dry methanol (25 ml),10% palladium hydroxide (1.9 g) was added and the solution washydrogenated at 200 psi for 24 hours. The solution was filtered overcelite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidinewhich was used as such for the subsequent step. A mixture of3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate(37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol)in methanol was stirred at room temperature for 24 hours. The reactionmixture was concentrated and partitioned between 250 ml EtOAc and 50 mlwater, dried over sodium sulfate, filtered and concentrated.Purification of the crude product by column chromatography (Hexane:EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil.To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine(2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) wereadded and the solution refluxed for 24 hours. The reaction mixture wascooled to room temperature, concentrated and partitioned between 40 mlchloroform and 5 ml water. The organic layer was dried over sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g(49%) of the required product as a colorless oil; ¹H-NMR (CDCl₃): δ 1.45(s, 9H),1.54-1.69 (m, 8H), 2.21-2.68 (m, 2H), 2.74-2.80 (m, 1H),3.02-3.22 (m, 4H), 5.41 (s, 1H), 7.13-7.17 (m, 1H), 7.33 (d, J=7.93 Hz,1H).7.63 (t, J=7.6 Hz, 1H), 8.54 (d, J=4.6 Hz, 1H). ToN-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine(0.15 g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroaceticacid was added and the solution stirred at room temperature for 1 hour.The solution was concentrated, neutralized with 10% KOH solution andextracted into 25 ml of dichloromethane. The organic layer was driedover sodium sulfate, filtered and concentrated to give 0.098 g (100%) of3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such forthe subsequent step (step h).

e. Methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate. A mixture of3,4-difluorobenzaldehyde (14.2 g, 0.1 mol), methyl acetoacetate (12.2 g,0.105 mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Starktrap for 8 hours. Benzene was. evaporated, the residue was dissolved inethyl acetate (200 mL) and washed with brine (50 mL), saturatedpotassium bisulfate solution (50 mL), and saturated sodium bicarbonatesolution in sequence. The ethyl acetate solution was dried (magnesiumsulfate), solvent removed under reduced pressure and the residue waspurified by column chromatography (SiO2, EtOAc/hexane, 10%-15%). Theproduct, methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate, wasobtained as a yellow oil (0.98 g, 98.3%) and was used in the next stepwithout any further characterization.

f.6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine.A mixture of methyl 2-{(3,4-difluorophenyl) methylene} 3-oxobutyrate(8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol),and NaHCO₃ (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at70° C. for 16 hours. The mixture was cooled, diluted with EtOAc (300 mL)and washed with water (5×300 mL), brine (300 mL), and dried (MgSO₄).Solvent was evaporated and the crude product was purified by flashcolumn chromatography on silica gel using 10% through 20% EtOAc inhexane as the gradient eluent, to leave the product as an oil (3.82 g,30.2%); ¹H-NMR (CDCl₃): δ 2.32,2.39 (2 s, 3H), 3.58, 3.64 (2 s, 3H),3.72, 3.85 (2 s, 3H), 5.55 (s, 1H), 6.13-7.8 (m, 4H).

g. 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine.

To a solution of6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine(2.82 g, 9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) inCH₂Cl₂ (50 mL),at 0-5° C., 4-nitrophenyl chloroformate (1.82 g, 9.04mmol) was added and the mixture was allowed to warm to room temperature.After 12. hours solvent was evaporated and the residue was purified byflash column chromatography (SiO₂, EtOAc/hexane, 10%-15%)to obtain theproduct as white crystals (3.72, 84.7%); m.p. 172-174° C.; ¹H-NMR(CDCl₃):b 2.51 (s, 3H), 3.72 (s, 3H), 3.97 (s, 3H), 6.26 (s, 1H),7.0-7.3 (m, 3H), 7.38 (d, J=9.3 Hz, 2H), 8.32 (d, J=9.3 Hz, 2H).

h.6-(3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride. To6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine(0.04 g,0.086 mmol) in 10 ml of dry dichloromethane,3-[4-(2-pyridyl)-piperidine-1-yl]propylamine (0.038 g, 0.17 mmol) wasadded and the solution was stirred at room temperature for 24 hours. Thereaction mixture was stirred for another 1 hour after addition of 2 mlof 6N HCl. After neutralization with 10% aqueous KOH solution, thereaction mixture was extracted into dichloromethane (3×10 ml). Theorganic layer was dried over sodium sulfate, filtered and concentrated.The crude product was purified by flash chromatography (EtOAc: MeOH,4.5:0.5) to give 0.040 g (89%) as a syrup ; ¹H-NMR (CDCl₃): δ 1.73-2.11(m, 7H), 2.41 (s, 6H), 2.69 (m, 1H), 3.04 (d, J=12.1 Hz, 2H), 3.31-3.48(m, 2H), 3.71 (s, 3H), 6.70 (s, 1H), 7.24-7.27 (m, 5H), 7.61 (t, J=8.0Hz, 2H), 8.51 (d, J=4.6 Hz, 1H), 8.89 (t, J=5.1 Hz, 2H).

To the free base (0.04 g, 0.07 mmol) in 4 ml of dichloromethane, 5 ml of1N HCl in ether was added, and the solution concentrated under reducedpressure. Recrystallization from ether gave 0.04.6 g (98%) of6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride as a white solid; m.p. 170-174° C.; Anal. Calcd. forC₂₇H₃₃Cl₂F₂N₅O₄. 1.0 H₂O: C, 52.43; H,5.70, N 11.30. Found: C, 52.16; H5.35; N 11.10.

EXAMPLE 22

6-(3,4-Benzofurazan-5-yl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidin-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride (Scheme 8).

5-Methylbenzfuroxan. 4-Methyl-2-nitroaniline (100 g, 0.650 mol) wassuspended in saturated alcoholic sodium hydroxide solution (1.50 1). Tothis suspension was added with cooling (5° C.) commercial aqueous sodiumhypochlorite till the red color disappeared. The fluffy yellowprecipitate formed was filtered, washed with cold water andrecrystallized from ethanol to get 5-Methylbenzfuroxan (88.2 g, 89 0%yield) as a pale solid.

5-Methylbenzofurazan. To 5-Methylbenzfuroxan (88.2 g, 0.59. mol) inrefluxing EtOH (75 ml) was added dropwise P(OEt)₃ (150 ml ). Whenaddition was complete, refluxing was continued for 1 more hour. Thesolvent was removed by rotary evaporation and the residue shaken withwater (200 mL) and allowed to stand overnight at (0˜5° C.). The brownsolid so obtained was filtered, washed with water and chromatograghed onsilica gel to yield 5-Methylbenzofurazan (70 g, 87%) as white needle.

5-Dibromomethylbenzofurazan. 5-Methylbenzofurazan (70 g, 0.52 mol), NBS(325 g), and benzoyl peroxide (0.5 g) were refluxed with stirring incarbon tetrachloride (1.5 L) with exclusion of moisture for 30 hours.The reaction mixture was washed with water (2×0.5L), dried (NaSO₄), andthe solvent was removed in vacuo. The residue was chromatographed(silica, EtOAc-hexane, 1:150) to give 122 g (80%) of the title compound.The resulting white solid was used in the next step without any furthercharacterization.

5-Formylbenzofurazan. To a refluxing mixture of thedibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 L) was addedAgNO₃ (163 g) in 2 L of water. Refluxing was continued for 2 hours. Themixture was cooled and the AgBr was removed by filtration throughCelite, and the solvent was concentrated to a small volume. Theresulting solution was extracted with toluene (10×100 mL), dried(MgSO₄), and the solvent was removed in vacuo. The residue waschromatographed on silica (EtOAc-hexane, 8:1000) to give 48.2 g of thetitle aldehyde (78%) as a white solid.

a. Methyl 2-{(benzofuran-5-yl)methylene}-3-oxobutyrate.

A mixture of 5-Formylbenzofurazan (0.6 g, 4.1 mmol), methyl acetoacetate(0.52 g, 4.5 mmol), piperidine (0.019 g, 0.225 mmol), and acetic acid(0.014 g, 0.225 mmol) in benzene (30 mL) was stirred and refluxed with aDean-Stark trap for 8 h. Benzene was evaporated, the residue wasdissolved in ethyl acetate (80 mL) and washed with brine (50 mL),saturated potassium bisulfate solution (50 mL), and saturated sodiumbicarbonate solution in sequence. The ethyl acetate solution was dried(magnesium sulfate), solvent removed under reduced pressure and theresidue was purified by column chromatography (SiO2, EtOAc/hexane,10%-15%). The product, methyl2-{(benzofuran-5-yl)methylene}-3-oxobutyrate, was obtained as an oil(0.98 g, 98.3%) and was used in the next step without any furthercharacterization.

b.6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine.A mixture of methyl 2-{(benzofuran-5-yl)methylene}-3-oxobutyrate (1.02g, 4.1 mmol), O-methylisourea hydrogen sulfate (1.06 g, 6.2 mmol), andNaHCO₃ (1.3 g, 16.4 mmol) in DMF (15 mL) was stirred and heated at 70°C. for 16 h. The mixture was cooled, diluted with EtOAc (50 mL) andwashed with water (5×50 mL), brine (50 mL), and dried (MgSO₄). Solventwas evaporated and the crude product was purified by flash columnchromatography on silica gel using 10% through 20% EtOAc in hexane asthe gradient eluent, to leave the product as an oil (0.52 g, 43%);¹H-NMR (CDCl₃): δ 2.38,2.42 (2 s, 3H), 3.60, 3.66 (2 s, 3H), 3.74, 3.82(2 s, 3H), 5.53, 5.68 (2 s, 1H), 6.31, 6.32 (br s, 1H), 7.0-7.8 (m, 3H).

c.6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbo nyl]pyrimidine.

To a solution of6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine(0.485 g, 1.6 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) inCH₂Cl₂ (20 mL),at 0-5° C., was added 4-nitrophenyl chloroformate (0.307g, 1.52 mmol) and the mixture was allowed to warm to room temperature.After 12 hours solvent was evaporated and the residue was purified byflash column chromatography (SiO2, EtOAc/hexane, 10%-15%)to obtain theproduct as white crystals (0.665 g, 89%); m.p. 180-183° C.; ¹H-NMR(CDCl₃): 2.54 (s, 3H), 3.75 (s, 3H), 3.98 (s, 3H), 6.37 (s, 1H), 7.40(d, J=9.3 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J=9.0Hz, 1H), 8.32 (d, J=9.3 Hz, 2H).

d.6-(3,4-Benzofurazan-5-yl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidin-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride. To6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine(0.04 g,0.085 mmol) in 10 ml of dry dichloromethane,3-[4-(2-pyridyl)-piperidine-1-yl]propylamine (0.037 g, 0.17 mmol) wasadded and the solution was stirred at room temperature for 24 hours. Thereaction mixture was stirred for another 1 hour after addition of 2 mlof 6N HCl. After neutralization with 10% aqueous KOH solution, thereaction mixture was extracted into dichloromethane (3×10 ml). Theorganic layer was dried over sodium sulfate, filtered and concentrated.The crude product was purified by flash chromatography (EtOAc: MeOH,4.5:0.5) to give 0.040 g (89%) as a syrup ; ¹H-NMR (CDCl₃): δ 1.74-2.10(m, 7H), 2.46 (s, 6H), 2.70-2.72 (m, 1H), 3.05 (d, J=12.1 Hz, 2H),3.34-3.48 (m, 2 H), 3.76 (s, 3H), 6.82 (s, 1H), 7.11-7.32 (m, 3H),7.54-7.78 (m, 4H), 8.53 (d, J=4.6 Hz, 1H), 8.89 ( t, J=5.16 Hz, 2H).

To the free base (0.04 g, 0.07 mmol)in 4 ml of dichloromethane, 5 ml of1N HCl in ether was added, and the solution concentrated under reducedpressure. Recrystallization from ether gave 0.040 g (87%) of6-(3,4-benzofurazan-5-yl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride as a white solid; m.p. 200-204° C.; Anal. Calcd. forC₂₇H₃₃Cl₂N₇O₅. 2.5 H₂O: C, 49.77; H,5.88. Found: C, 49.41; H 5.20.

EXAMPLE 23

6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethylpyrimidine(Scheme 9). a.6-(3,4-Difluorophenyl)-1,6-dihydro-2,4-dimethyl-5-methoxycarbonylpyrimidine.To a solution of acetamidine hydrochloride (1.53 g, 16.2 mmol.) in DMF(10 mL) were added a solution of potassium tert-butoxide (1.33 g, 11.8mmol.) in DMF (10 mL) and a solution of methyl {2-(3,4-difluorophenyl)methylene}-3-oxobutanoate (2.6 g, 10.8 mmol.) in DMF (10 mL) at 0° C.After the mixture was stirred for 0.5 hour at 0° C., p-toluenesulfonicacid monohydrate (4.1 g, 21.5 mmol.) was added. The mixture was heatedat 100-120° C. for 2 hrs. The reaction mixture was cooled to roomtemperature, quenched with aqueous NaOH solution (2N, 60 mL), andextracted with ether. The organic layer was dried over Na₂SO₄ andevaporated. The residue was flash chromatographed over silica gel(eluent: ethyl acetate) to give the product in 59% yield (1.8 g) as ayellow solid: ¹H NMR (300 MHz, CDCl₃): δ 1.98 (3H, s), 2.31 (3H, s),3.59 (3H, s), 5.47 (1H, s), 7.03-7.05 (3H, m).

b.1-(5-Chloropentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-2,4-dimethyl-5-methoxycarbonylpyrimidine.To a suspension of NaH (90 mg, 60% dispersion in mineral oil, 2.25mmol.) in THF (7 mL) was added a solution of the above yellow solid (0.6g, 2.14 mmol.) in THF (8 mL) at 0° C. After 20 min,1-bromo-5-chloropentane (1 mL, d 1.408, 7.59 mmol.) was added. Thereaction mixture was then refluxed overnight. After the removal of thesolvent, the residue was flash chromatographed over silica gel (eluent:ethyl acetate) to give the product in 75% yield (0.614 g) as a yellowoil: ¹H NMR (300 MHz, CDCl₃): δ 1.42-1.75 (6H, m), 2.17 (3H, s), 2.28(3H, s), 3.05-3.45 (2H, m), 3.49 (2H, t, J=5.88 Hz), 3.63 (3H, s), 5.23(1H, s), 7.01-7.15 (3H, m)

c.6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethylpyrimidine.

A mixture of the above yellow oil (0.667 g, 1.73 -mmol.),4-methoxycarbonyl-4-phenyl piperidine (0.76 g, 3.47 mmol.), potassiumcarbonate (0.96 g, 6.95 mmol.), sodium iodide (0.52 g, 3.47 mmol.) and1,4-dioxane (15 mL) was refluxed overnight. The undissolved solid wasthen filtered off and the solvent was evaporated. The residue was flashchromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2Mammonia in methanol) to give the title compound in 78% yield (0.768 g)as a yellow oil: CIMS, m/z 568 (MH⁺); ¹H NMR 7. (300 MHz, CDCl₃): δ1.23-1.28 (2H, m), 1.43-1.51 (2H, m), 1.77-2.13 (8H, m), 2.16 (3H, s),2.28 (3H, s), 2.47-2.55 (2H, m), 2.74-2.81 (2H, m), 3.00-3.12 (1H, m),3.22-3.38 (1H, m), 3.613 (3H, s), 3.615 (3H, s), 5.22 (1H, s), 6.99-7.35(3H, m).

Treatment of the free base with 2 equivalents of 1M HCl in ether gavethe HCl salt as a yellow foam: m.p. 170-176° C. Anal. Calc. forC₃₂H₃₉F₂N₃O₄.2HCl.2.3H₂O: C, 56.35; H, 6.74; N, 6.16; Found: C, 56.34;H, 6.62; N, 5.86.

EXAMPLE 24

(+)-6-(3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-(2-pyridyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride.

A solution of(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (0.894 g, 2 mmol),3-[4-(2-pyridyl)-4-hydroxypiperidin-1-yl]propylamine (0.517 g, 2.2 mmol)in tetrahydrofuran (100 mL) was stirred at room temperature for 24hours. The reaction mixture was stirred for another 1 hour afteraddition of 2 ml of 6N HCl. Solvent was evaporated at reduced pressureand the residue was basified by treatment with 10% aqueous KOH solution,extracted with dichloromethane (3×10 mL). The combined extracts weredried over potassium carbonate, and solvent evaporated. The crudeproduct was purified by flash chromatography on silica gel(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to give 1.20 g (97%) asa syrup. The free base was dissolved in 20 mL anhydrous ether, cooled to0-5° C. and treated with 10 mL of 1N HCl in ether. The white powder wasfiltered and dried to give6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-(2-pyridyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydropyrimidinedihydrochloride; m.p. 200-206° C.; [α]_(D)=+91 (c=1.15 g, in 100 mL ofchloroform). Anal. Calcd. for C₂₇H₃₃Cl₂F₂N₅O₄. 0.4CHCl₃: C, 48.18; H,4.92; N, 10.18. Found: C, 48.34; H, 5.01; N, 10.08.

EXAMPLE 25

(+)-1,2,3,6-Tetrahydro-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-(2-hydroxypropyl)}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine dihydrochloride

a) 3-[4-(2-Pyridyl)-piperidin-1-yl] (2-hydroxypropyl) phthalimide

A mixture of 4-(2-pyridyl)piperidine (3.25 g, 19.90 mmol) and2,3-epoxypropylphthalimide (4.449 g, 21.89 mmol) in DMF (20 mL) wasstirred and heated at 70° C. for 48 h. The solvent was evaporated underreduced pressure and the residue was purified by column chromatographyon silica gel using chloroform-methanol-2M ammonia in methanol(1000/28/14) as the eluent, to obtain the desired product as a viscousoil (6.15 g, 84%).

b) 3-[4-(2-Pyridyl)-piperidin-1-yl]-2-hydroxy propylamine

A mixture of 3-[4-(2-pyridyl)-piperidin-1-yl](2-hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) andhydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred andrefluxed for 4.5 h. It was cooled, filtered, and the solid was washedwith methanol (30 mL). Evaporation of solvent from the filtrate gave theproduct as a viscous oil (0.85 g, 98%).

c) (+)-1,2,3,6-Tetrahydro-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-(2-hydroxypropyl) )carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine dihydrochloride

A solution of(+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (105 mg, 0.23 mmol),3-[4-(2-pyridyl)piperidin-1-yl]-2-hydroxypropylamine (50 mg, 0.23 mmol)in tetrahydrofuran (20 mL) was stirred at room temperature for 24 hours.Solvent was evaporated at reduced pressure and the residue was basifiedby treatment with 10% aqueous KOH solution, extracted withdichloromethane (3×10 mL). The combined extracts were dried overpotassium carbonate, and solvent evaporated. The crude product waspurified by flash chromatography (dichloromethane:MeOH:2M ammonia inMeOH,90:8:4) to give 120 mg (97%5) as a syrup; The HCl salt was preparedby treatment with 1N HCl in ether; m.p. 215-220° C.; [α]_(D)=+41 (c=1.15g, in 100 mL of methanol). Anal. Calcd. for C₂₇H₃₃N₅O₆F₂Cl₂. 0.8 MeOH:C, 52.00; H, 5.68; N, 10.90. Found: C, 52.08; H; 5.70; N, 10.53.

EXAMPLE 26 AND EXAMPLE 27

(+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidin-1-yl)-(2-fluoro)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrim idinedihydrochloride

A mixture of(+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine (0.50 g, 0.92 mmol), diethylaminosulfurtrifluoride (DAST, 0.222 g, 1.38 mmol, 1.5 eq.), and benzene (50 mL) wasstirred at 70 ° C. under dry argon atmosphere for 24 h. The TLC analysisof reaction mixture showed the complete disappearance of the startingmaterial. Solvent was evaporated under reduced pressure and the residuewas purified by column chromatography on silica gel (20 g), usingchloroform/methanol/2 M ammonia in methanol (500/16/8) as the eluent togive two products as a mixture of two diastereomers. These diastereomerswere purified by chiral HPLC separation on Chiralpak A3, 4.6×250 mmcolumn, using isocratic condition (90% hexane and 10% ethanol containing0.5% DEA). The retention time for the first product (example 26) was12.97 minutes and for the second product (example 27) was 16.18 minutes.The combined yield of these products is (65 mg +65 mg) 24%. The HCl saltwas prepared by treatment with 1N HCl in ether; Example 26: m.p.132-134° C.; [α]_(D)=+108 (c=0.715 g, in 100 mL of chloroform). Anal.Calcd. for C₂₈H₃₂N₅O₄F₃Cl₂. 2.0 H₂O: C, 53.38; H, 5.60; N, 11.12. Found:C, 53.28; H; 5.89; N, 10.96. Example 27: m.p. 130-132° C.; [α]_(D)=+100(c=0.7 g, in 100 mL of chloroform). Anal. Calcd. for C₂₈H₃₂N₅O₄F₃Cl₂.1.5H₂O: C, 54.15; H, 5.52; N, 11.28. Found: C, 54.17; H; 5.57; N, 11.00.

Note: Examples 26 and 27 are two diastereomeric products derived fromthe (+)enantiomer at the pyrimidine part and the two possibleenantiomeric compounds with respect to the fluoromethylene chiralcenter.

EXAMPLE 28

(+)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

a) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide.

A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol),3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate(276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirredand heated at 100-110° C. for 8 h. About 80% of the solvent wasevaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96-98° C.

b) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine.

To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl) propylphthalimide(112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added andthe mixture was stirred and refluxed for 20 h. It was cooled, the whitesolid formed was filtered and washed with more methanol (200 mL).Solvent was evaporated from the filtrate and residue was dried undervacuum for 4 h. Chloroform (500 mL) was added to this, stirred for 1 hand filtered. The white solid was washed with more chloroform (200 mL),the solvent was evaporated from the combined filtrates to leave theproduct as an oil (70 g, 96%).

c) Benzyl 2-[(2,4-difluorophenyl)methylene]-3-oxopentanoate. A solutionof benzyl propionylacetate (157 g, 0.758 mol), 2,4-difluorobenzaldehyde(107.65 g, 0.758 mol), and piperidinium acetate (5.49 g, 38 mmol) inbenzene (1 L) were stirred at room temperature for 96 h. The mixture waswashed with water (2×100 mL), dried (magnesium sulfate) and the solventevaporated under reduced pressure to get the product as a pale yellowsyrup (251.2 g). It was used in the next step without furtherpurification.

d)5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine.

A suspension of benzyl 2-[(2,4-difluorophenyl)methylene]-3-oxopentanoate (80.0 g, 0.241 mol), 0-methylisoureahemisulfate (63.8 g, 0.362 mol, 1.5 eq.), NaHCO₃ (60.48 g, 0.72 mol) inethanol (800 mL) was stirred at 60-70 (C for 20 h. After cooling to roomtemperature, the mixture was filtered, and the solid was washed withethanol (200 mL). The solvent was evaporated from the combined filtratesand the residue was purified by column chromatography (SiO₂,EtOAc/Hexane, 10%-30%) to get5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine as a pale yellow oil (39 g, 42%). The ¹H-NMR analysis showedit to be a mixture of amine/imine tautomers and was used as is in thenext step.

e)5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethyl amino)pyridine (9.3g, 75.8 mmol) in CH₂Cl₂ (200 mL) was added a powder of 4-nitrophenylchloroformate (15.3 g, 75.8 mmol) at 0° C. The reaction mixture wasstirred for 12 h at room temperature and then water (50 mL) was added.The pH of the aqueous layer was adjusted to 10-11 by the addition of 6 Nsodium hydroxide. The dichloromethane layer was separated and dried(Na₂SO₄). Solvent was evaporated in vacuo and the residue was purifiedby column chromatography (SiO₂, dichloromethane /hexane, 20%-50%) togive the product as a viscous oil (32.0 g, 98%).

f) 5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4-difluorophenyl) pyrimidine.

To a stirred solution of5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(32 g, 58.17 mmol) in dichloromethane (200 mL) was addedR-(+)-(-methylbenzylamine (9.16, 75.6 mmol) at room temperature and thestirring was continued for 12 h. The mixture was diluted with moredichloromethane (200 mL) and washed with 0.5 N NaOH solution (2×60 mL).The organic layer was dried over Na₂SO₄, filtered and solvent wasevaporated. The resulting mixture of diastereomers was separated bycolumn chromatography(SiO₂, 3% EtOAc in toluene). The first majorproduct to elute was(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4-difluorophenyl)pyrimidine (12.15 g,38%). [α]_(D)=+214 (c=1.5 g in 100 mL CHCl₃); The second major productto elute was the other diastereomer and no effort was made to isolateit.

g)(+)-5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine.

To a stirred solution of(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4-difluorophenyl)pyrimidine(11.15 g, 20.41 mmol) in toluene (250 mL) was added1,8-diazabicyclo[5,4,01-undec-7-ene (4.04 g, 26.53 mmol) and the mixturewas stirred at room temperature for 14 h. The solvent was evaporated andthe residue was purified by flash column chromatography on silica gelwith 3:1 EtOAc/hexane as eluent to give(+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidineas a viscous oil (6.15 g, 78%).

h)(+)-5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine (4.1 g,10.62 mmol) and 4-(N,N-dimethylamino)pyridine (1.69 g, 13.80 mmol) inCH₂Cl₂ (200 mL) was added a powder of 4-nitrophenyl chloroformate (2.78g, 13.80 mmol) at room temperature. The reaction mixture was stirred for12 h and washed with 0.5 N NaOH solution (2×50 mL). The organic layerwas separated and dried (Na₂SO₄). The solvent was evaporated and theresidue was purified by column chromatography on silica gel usingdichloromethane/hexane (20%-50%) as the eluent to give(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(5.37 g, 92%) as a viscous oil.

i)(+)-5-(Benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (6.50 g, 11.81 mmol) and3-[4-cyano-4-phenylpiperidin-1-yl]propylamine (3.60 g, 15.36 mmol) inTHF (500 mL) was stirred at room temperature for 18 h. It was cooled to0° C. and 10% HCl in water (2 mL) was added and stirred for 2 h. Themixture was washed with 0.5 N aq. NaOH solution (30 mL), dried overNa₂SO₄ and the solvent evaporated. The residue was purified by columnchromatography on SiO₂ using CHCl₃/MeOH/2M NH₃ in MeOH (100/2/1) aseluent to obtain(+)-5-(benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-ethyl-1-{N[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidineas a white foamy solid (7.05 g, 93%).

j)6-(2,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylicacid.

To a suspension of 10% Pd—C (2.1 g) in MeOH (100 mL) and H₂O (20 mL) wasadded a solution of(+)-5-(benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine(7.55 g, 11.2 mL) in methanol (100 mL) and the mixture was hydrogenatedat 80 psi for 14 h. The black suspension was filtered through a pad ofcelite and washed thoroughly with MeOH (2.0 L) and methanol/chloroform(1:2, 200 mL). Solvent was evaporated from the combined filtrate toleave the product(+)-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylicacidasa white solid (6.06 g, 98%). It was used in the next step withoutfurther purification.

k)(+)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of(+)-6-(2,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylicacid (6.30 g, 11.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (4.29 9, 22.36 mmol, 2 eq.), and4-(N,N-dimethylamino)pyridine (3.41 g, 27.95 mmol, 2.5 eq) in anhydrousdichloromethane (400 mL) was stirred at room temperature for 2 h. Tothis, 40% aqueous ammonia (6.13 g, 5 eq) was added and the stirring wascontinued for 12 h. The mixture was diluted with 200 mL ofdichloromethane and washed with saturated aqueous ammonium chloridesolution (3×200 mL). Solvent was evaporated from the dried (sodiumsulfate) dichloromethane solution and the residue was purified by columnchromatography on silica gel using chloroform-methanol-2M ammonia inmethanol (100/2/1) as the eluent, to obtain the desired product as awhite powder (5.45 g, 87%); m.p. 210-211° C.; Part of the compound (300mg) was dissolved in dichloromethane (3 mL), cooled to 0-5° C. andtreated with 1N HCl in ether (10 mL) followed by anhydrous ether (20mL). The white powder formed was filtered, washed with ether (100 mL)and dried (320 mg, 100%); m.p. 196-97° C.; [α]_(D)=+126 (c=0.505 g, in100 mL of 1:1 chloroform/MeOH). Anal. Calcd. for C₂₉H₃₃N₆O₃F₂Cl: C,59.27; H, 5.78; N, 14.24. Found: C, 59.33; H; 5.67; N, 14.32.

EXAMPLE 29

(+)-5-Carboxamido -6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine dihydrochloride.

a) 2-Cyanoethyl 4-methoxyacetoacetate.

A mixture of methyl 4-methoxyacetoacetate (50 g, 0.342 mol) and3-hydroxypropionitrile (31.61 g, 0.444 mol) was heated to 160-180° C. ina distillation set-up. It was kept at that temperature for 2 h until thedistillation of the methanol stopped. The residual yellow oil of2-cyanoethyl 4-methoxyacetoacetate (56.4 g, 90%) was used as is withoutany further purification.

b) 2-Cyanoethyl2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate.

A solution of 2-cyanoethyl 4-methoxyacetoacetate (17.8 g, 0.125 mol),3,4-difluorobenzaldehyde (25.5 g, 6.26 mmol), acetic acid (0.3769, 6.26mmol), and piperidine (0.533 g, 6.26 mmol) in benzene (500 mL) wereadded molecular sieves (200 g) and the mixture was stirred at roomtemperature for 24 h. Then the solvent was evaporated under reducedpressure and the residue was purified by column chromatography usingchloroform/ethyl acetate (100:5) to get the product as an oil (29 g,75%).

c)5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.

A suspension of 2-cyanoethyl2-[(3,4-difluorophenyl)methylene]-3-oxo-4—methoxybutyrate (29 g, 0.094mol), O-methylisourea hemisulfate (21 g, 0.121 mol, 1.3 eq.),dimethylaminopyridine (29.67 g, 0.243 mol, 2.5 eq.) in ethanol (400 mL)was stirred at 50-55 ° C. for 6 h. The solvent was evaporated from thecombined filtrates and the residue was purified by column chromatography(SiO₂, EtOAc/hexane, 10%-30%) to get5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidineas a pale yellow oil (10.5 g, 31%). The ¹H-NMR analysis showed it to bea mixture of amine/imine tautomers and was used as is in the next step.

d)5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of 5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(10.5 g, 28.74 mmol) and 4-(N,N-dimethylamino)pyridine (6.95 9, 34.49mmol) in CH₂Cl₂ (100 mL) was added a powder of 4-nitrophenylchloroformate (4.21 g, 34.49 mmol) at 0° C. The reaction mixture wasstirred for 12 h at room temperature and then the solvent wasevaporated. The residue was purified by column chromatography (SiO₂,dichloromethane/hexane, 20%-50%) to give the product as a viscous oil(6.5 g, 43%).

e) 5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophonyl)pyrimidine.

To a stirred solution of5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(6.5 g, 12.25 mmol) in dichloromethane (150 mL) was addedR-(+)-α-methylbenzylamine (1.78 g, 14.7 mmol) at room temperature andthe stirring was continued for 12 h. Solvent was evaporated and theresidue was purified by column chromatography (SiO₂, 10-20% EtOAc inhexane). The first major product to elute was(+)-5-(2-cyanoethoxycarbonyl)-4-methoxmethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine (2.54 g,44.5%) [α]_(D)=+177.8 (c=9.2 g in 100 mL CHCl₃); The second majorproduct to elute was the other diastereomer and no effort was made toisolate it.

f)(+)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine.

To a stirred solution of(+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine(2.80 g, 5.46 mmol) in toluene (80 mL) was added1,8-diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol) and the mixturewas stirred at 75° C. for 1 h. The solvent was evaporated and theresidue was purified by flash column chromatography on silica gel with3:1 EtOAc/hexane as eluent to give(+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidineas a viscous oil (0.82 g, 40.5%).

g)(+)-5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of(+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(0.82 g, 2.24 mmol) and 4-(N,N-dimethylamino)pyridine (0.329 g, 2.69mmol) in CH₂Cl₂ (200 mL) was added a powder of 4-nitrophenylchloroformate (0.543 g, 2.69 mmol) at room temperature. The solvent wasevaporated and the residue was purified by column chromatography onsilica gel using dichloromethane/hexane (20%-50%) as the eluent to give(+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.80 g, 67%) as a viscous oil.

h)(+)-5-(2-Cyanoethoxycarbonyl)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of(+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine(0.44 g, 0.83 mmol) and 3-[4-(2-pyridyl)piperidin-1-yl]propylamine(0.218 g, 0.996 mmol) in THF (15 mL) was stirred at room temperature for12 h. It was cooled to 0° C. and 10% HCl in water (2 mL) was added andstirred for 2 h. Solvent was evaporated and the residue was purified bycolumn chromatography on SiO₂ using CHCl₃/MeOH/2M NH₃ in MeOH (100/2/1)as eluent to obtain(+)-5-(2-cyanoethoxycarbonyl)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-(3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine as a white foamysolid (0.41 g, 83%).

i)6-(3,4-Difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylicacid.

To a stirred solution of(+)-5-(2-cyanoethoxycarbonyl)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine(0.34 g, 0.57 mmol) in acetone (5 mL) at 0° C., sodium hydroxidesolution (1 N, 1.71 mL) was added drop wise and the stirring wascontinued until the disappearance of the starting material (1 hour).Most of the acetone from the mixture was evaporated under reducedpressure while keeping the temperature at 0° C. and the residue wasadjusted to pH 7.0 by the addition of 1N hydrochloric acid. The whiteprecipitate of6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylicacid formed was filtered and dried under vacuum (0.30 g, 96%).

j)(+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of(+)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid(0.30 g, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.212 9, 1.1 mmol, 2 eq.), and4-(N,N-dimethylamino)pyridine (0.134 g, 1.1 mmol, 2 eq) in anhydrousdichloromethane (20 mL) was stirred at room temperature for 2 h. Tothis, 40% aqueous ammonia (0.64 g, 10 eq) was added and the stirring wascontinued for 12 h. The mixture was diluted with 20 mL ofdichloromethane and washed with saturated aqueous ammonium chloridesolution (3×200 mL). Solvent was evaporated from the dried (sodiumsulfate) dichloromethane solution and the residue was purified by columnchromatography on silica gel using chloroform-methanol-2M ammonia inmethanol (100/2/1) as the eluent, to obtain the desired product as awhite powder (0.232 g, 78%); The HCl salt of this compound was preparedby treatment with 1 N HCl in ether. m.p. 95-97° C.; [α]_(D)=+139 (c=2.1g, in 100 mL of chloroform). Anal. Calcd. for C₂₇H₃₄N₆O₄F₂Cl₂. 2.2 H₂O:C, 49.50; H, 5.91; N, 12.83. Found: C, 49.50; H, 5.89; N, 12.43.

EXAMPLE 30

(+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of(+)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid(0.30 g, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.212 g, 1.1 mmol, 2 eq.), and 4-(N,N-dimethylamino)pyridine (0.134 g, 1.1 mmol, 2 eq) in methanol (20 mL) was stirred atroom temperature for 20 h. Solvent was evaporated and the residue wasdissolved in 20 mL of dichloromethane and washed with saturated aqueousammonium chloride solution (3×200 mL). Solvent was evaporated from thedried (sodium sulfate) dichloromethane solution and the residue waspurified by column chromatography on silica gel usingchloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, toobtain the desired product as a white powder (278 mg, 91%); The HCl saltof this compound was prepared by treatment with 1 N HCl in ether. m.p.180-184° C.; [α]_(D)=+122 (c=1.25 g, in 100 mL of methanol) Anal. Calcd.for C₂₈H₃₁N₅O₅F₂Cl₂. 1.0 H₂O: C, 51.86; H, 5.75; N, 10.80. Found: C,52.14; H, 5.72; N, 10.53.

EXAMPLE 31

(+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-oxo)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethyl pyrimidinedihydrochloride

a) Methyl 2-[(3,4-difluorophenyl) methylene]-3-oxo-4-methoxybutyrate.

A solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol),3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate(5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400g) and the mixture was stirred at room temperature for 48 h. Themolecular sieves were removed by filtration and the solvent wasevaporated from the filtrate under reduced pressure. The residue waspurified by column chromatography on silica gel using chloroform/ethylacetate (100:3) to get the product as an oil (67 g, 47%).

b)5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.

A suspension of methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate (7.50 g, 27.75 mmol), O-methylisoureahemisulfate (7.17 g, 41.63 mmol, 1.5 eq.), sodium bicarbonate (6.99 g,83.25 mmol, 3 eq.) in ethanol (400 mL) was stirred at 50-55° C. for 6 h.The solvent was evaporated from the combined filtrates and the residuewas purified by column chromatography (SiO₂, EtOAc/hexane, 10%-30%) toget5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidineas a pale yellow oil (4.3 g, 47%). The ¹H-NMR analysis showed it to be amixture of amine/imine tautomers and was used as is in the next step.

c)5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(4.3 g, 13.18 mmol) and 4-(N,N-dimethylamino)pyridine (2.09 g, 17.13mmol) in CH₂Cl₂ (100 mL) was added a powder of 4-nitrophenylchloroformate (3.45 g, 17.13 mmol) at 0° C. The reaction mixture wasstirred for 12 h at room temperature and the solid formed was removed byfiltration. Solvent was evaporated from the filtrate and the residue waspurified by column chromatography (SiO₂, dichloromethane/hexane,20%-50%) to give the product as a viscous oil (3.85 g, 59%).

d)5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-1-(N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine.

To a stirred solution of5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (3.82 g, 7.77 mmol) in THF (140 mL) was addedR-(+)-α-methylbenzylamine (1.13 g, 9.33 mmol, 1.2 eq.) at roomtemperature and the stirring was continued for 12 h. Solvent wasevaporated and the residue was purified by column chromatography (SiO₂,10-20% EtOAc in hexane). The first major product to elute was(+)-5-methoxycarbonyl-4-methoxmethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine(1.74 g, 44.5). [α]_(D)=+205.5 (c=5.1 g in 100 mL CHCl₃); The secondmajor product to elute was the other diastereomer and no effort was madeto isolate it.

e)(+)-5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.

To a stirred solution of(+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine(1.74 g, 3.67 mmol) in toluene (40 mL) was added1,8-diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol) and the mixturewas stirred at 70-80° C. for 1.5 h. The solvent was evaporated and theresidue was purified by flash column chromatography on silica gel with9:1 CHCl₃/EtOAc as eluent to give(+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidineas a viscous oil (1.11 g, 92.5%).

f)(+)-5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.

To a well stirred solution of(+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(1.11 g, 3.4 mmol) and 4-(N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol)in CH₂Cl₂ (200 mL) was added a powder of 4-nitrophenyl chloroformate(0.891 g, 4.42 mmol) at room temperature. The solvent was evaporated andthe residue was purified by column chromatography on silica gel usingCHCl₃/EtOAc (20%-50%) as the eluent to give(+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.30 g, 78%) as a viscous oil. [α]_(D)=+262.2 (c=2.3 g in100 mL CHCl₃).

g)(+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxyme thylpyrimidine.

A solution of(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenoxy)carbonylpyrimidine(0.450 g, 0.91 mmol),3-[4-(2-pyridyl)piperidin-1-yl]-2-hydroxypropylamine (0.280 g, 1.19mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24hours. The reaction mixture was stirred for another 1 hour afteraddition of 2 ml of 6N HCl. Solvent was evaporated at reduced pressureand the residue was basified by treatment with 10% aqueous KOH solution,extracted with dichloromethane (3×10 mL). The combined extracts weredried over potassium carbonate, and solvent evaporated. The crudeproduct was purified by flash chromatography (dichloromethane:MeOH:2Mammonia in MeOH,90:8:4) to give 0.514 g (98%) as a syrup.

h)(+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-oxo)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethyl pyrimidinedihydrochloride

To a stirred solution of DMSO (0.174 g, 2.23 mmol) in dichloromethane (5mL) at −78° C., oxalyl chloride (0.135 g, 1.07 mmol) in dichloromethane(5 mL) was added and the mixture was stirred for 3 min. To this, asolution of(+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxyme thylpyrimidine(0.51 g, 0.889 mmol) in dichloromethane (5 mL) was added and thestirring was continued for 15 min. It was warmed to room temperature andadded 5 mL of water. The pH of the mixture was adjusted to 10-11 byadding 1N NaOH and the dichloromethane layer was separated. The aqueouslayer was extracted with more dichloromethane (3×10 mL). The combineddichloromethane extracts were dried (magnesium sulfate), solventsevaporated, and the residue was purified by flash chromatography(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to give 0.32 g (63%) ofthe product as a syrup. [α]_(D)=+122 (c=0.55 g in 100 mL CHCl₃); Anal.Calcd. for C₂₉H₃₃N₅O₆F₂Cl₂. 2.5 H₂O: C, 48.77; H, 5.55; N, 10.16. Found:C, 48.71; H, 5.72; N, 9.87.

EXAMPLE 32 AND EXAMPLE 33

Syn and anti isomers of(+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroximino)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethylpyrimidine dihydrochloride

A solution of(+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidin-1-yl)-(2-oxo)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethylpyrimidine (0.14 g, 0.22 mmol), hydroxylaminehydrochloride (19.6 mg, 0.28 mmol), and sodium acetate (74.8 mg, 0.55mmol) in methanol (5 mL) was stirred at room temperature for 24 h.Solvent was evaporated at reduced pressure, the residue was mixed withdichloromethane (30 mL) and washed with water. The dichloromethanesolution was dried (sodium sulfate) and the solvent evaporated. Theresidue was purified by column chromatography on silica gel(chloroform:MeOH:2M ammonia in MeOH,90:8:4). The first product to elutewas Example 32, syn isomer with respect to oxime hydroxyl and piperidine(30 mg); [α]_(D)=+94.1 (c=0.528 g in 100 mL CHCl₃); The HCl salt wasprepared by treatment with 1N HCl in ether; m.p. 90-92 ° C.; Anal.Calcd. for C₂₈H₃₄N₆O₆F₂Cl₂. 1.5 H₂O.0.6 CH₂Cl₂: C, 47.65; H, 5.35; N,11.26. Found: C, 47.67; H; 5.56; N, 11.36.

The second product to elute was example 33, anti isomer with respect tooxime hydroxyl and piperidine (70 mg); [α]_(D)=+104 (c=0.3 g in 100 mLCHCl₃); The HCl salt was prepared by treatment with 1N HCl in ether;m.p. 103-105° C.; Anal. Calcd. for C₂₈H₃₄N₆O₆F₂Cl₂.2.2 H₂O.0.22 CH₂Cl₂:C, 47.74; H, 5.51; N, 11.84. Found: C, 48.01; H,. 5.72; N, 11.57.

EXAMPLE 34

(+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-methoximino)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethylpyrimidine dihydrochloride

A solution of(+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-oxo)propyl]}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethylpyrimidine(30 mg, 0.047 mmol), O-methoxylamine hydrochloride (7.78 mg, 0.093mmol), and sodium acetate (32 mg, 0.24 mmol) in methanol (5 mL) wasstirred at room temperature for 24 h. Solvent was evaporated at reducedpressure, the residue was mixed with dichloromethane (30 mL) and washedwith water. The dichloromethane solution was dried (sodium sulfate) andthe solvent evaporated. The residue was purified by columnchromatography on silica gel (chloroform:MeOH:2M ammonia inMeOH,90:8:4). Only one isomeric product was detected by thispurification (20 mg, 71%); [α]_(D)=+98 (c=0.4 g in 100 mL CHCl₃); TheHCl salt was prepared by treatment with 1N HCl in ether; m.p. 109-112°C.; Anal. Calcd. for C₂₉H₃₆N₆O₆F₂Cl₂. 2.3H₂O. 0.46 CH₂Cl₂: C, 46.93; H,5.55; N, 11.15. Found: C, 47.08; H, 5.66; N, 10.88.

EXAMPLE 35

(±)-1,2,3,6-Tetrahydro-1-{N -[3-(4-(2-carboxamidophenyl)-piparazin-1-yl)-propyl]}carboxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me thylpyrimidinedihydrochloride

a) 3-{(3,4,5-Trifluorophenyl)methylene}-2,4-pentanedione.

A mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol),2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol)inbenzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8hours. Benzene was evaporated, the yellow oily residue,2-{(3,4,5-trifluorophenyl)methylene}-2,4-pentanedione, was used in thenext step without any further purification.

b)6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine.

A mixture of 2-{(3,4,5-trifluorophenyl)methylene}-2,4-pentanedione (26.2mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO₃(6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 °C. for 6 hours. The mixture was filtered, the solid residue was washedwith ethanol (100 mL). Solvent was evaporated from the combined filtrateand the crude product was purified by flash column chromatography onsilica gel using 10% through 25% EtOAc in hexane as the gradient eluent,to leave the product as an oil (2.80 g, 36%).

c)6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine

To a solution of6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine(2.8 g, 9.38 mmol) and pyridine (10 mL) in CH₂Cl₂ (200 mL) at 0-5° C.,4-nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added and themixture was allowed to warm to room temperature. After 12 hours solventwas evaporated and the residue was purified by flash columnchromatography (SiO₂, dichloromethane/EtOAc, 10%-15%)to obtain theproduct as a white powder (4.0 g, 92%).

d)6-(3,4,5-Trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim idine.

To a well-stirred solution of6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim idine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5° C., 6Naqueous HCl (4 mL) was added and the mixture was allowed to warm to roomtemperature. After 2 h, solvent was evaporated and the product driedunder vacuum. The product was obtained as a pure single component and noneed for further purification (3.88 g, 100%).

e)(±)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-carboxamidophenyl)-piperazin-1-yl)-propyl]}carboxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me thylpyrimidinedihydrochloride

A mixture of 6-(3,4,5-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine(44.9 mg, 0.1 mmol) and3-[4-(2-carboxamidophenyl)-piperazin-1-yl]-propylamine (26.2 mg, 0.1mmol) in THF (10 mL) was stirred at room temperature for 10 h and thesolvent evaporated. It was redissolved in dichloromethane (10 mL),washed with ice-cold 0.5 N NaOH (2×5 mL), dried and solvent evaporated.The residue was purified by preparative thin layer chromatography onsilica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) asthe eluent to afford the product as a white powder (60 mg, 93%); The HClsalt was prepared by treatment with 1N HCl in ether to give the productas a dihydrochloride salt. Anal. Calcd. for C₂₈H₃₃N₆O₄Cl₂F₃0.4 H₂O: C,51.52; H. 5.22; N, 12.88. Found: C, 51.70; H, 5.25; N, 12.53.

EXAMPLE 36

1,2,3,6-Tetrahydro-1-{N-[3-(4-(4-fluorobenzoyl) piperidin-1-yl)ethyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride

a).6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine.

A well stirred solution of6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine(10 g) in THF (200 mL) at room temperature, aqueous 6N hydrochloric acid(10 mL) was added and the stirring was continued for 3 h. Solvent wasevaporated and the residue was dried under vacuum to obtain the productas a white powder (9.7 g, 100%); m.p. 185-186° C.

b)6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(2-bromoethylaminocarbonyl)pyrimidine.

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (0.5 g, 1.118 mmol), 2-bromoethylamine hydrobromide(0.458 g, 2.237 mmol), and potassium carbonate (2.0 g) in THF/water (50mL/5 mL) were stirred at room temperature for 1 h. Then most of thesolvent was evaporated at reduced pressure. The residue was partitionedbetween dichloromethane and water (100 mL and 100 mL). Thedichloromethane layer was separated, washed with ice-cold 0.5 N NaOH(2×50 mL) and dried (sodium sulfate). Evaporation of the solvent gavethe product as a single product (0.48 g, 100%) as a white powder; m.p.159-160° C.

c)1,2,3,6-Tetrahydro-1-{N-[2-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidinehydrochloride

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(2-bromoethylaminocarbonyl)pyrimidine (43 mg, 0.1 mmol), 4-(4-fluorobenzoyl)piperidinep-toluene sulfonate (57 mg, 0.15 mmol), potassium carbonate (300 mg),and potassium iodide (30 mg) in THF(10 mL) was stirred at roomtemperature for 20 h. The solid material was removed by filtration, thesolvent from the filtrate was evaporated, and the residue was purifiedby preparative thin layer chromatography on silica gel usingchloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent toafford the product as a viscous oil which was converted to the HCl saltby treatment with 1N HCl in ether; m.p. 159-160° C.; Anal. Calcd. forC₂₉H₂₉N₄O₅F₃.1HCl.0.8Et₂O: C, 57.27; H, 5.85; N, 8.56. Found: C, 57.31;H; 5.75; N, 8.79.

EXAMPLE 37

1,2,3,6-Tetrahydro-1-{N-[3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl -6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride

a)6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine.

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (1.0 g, 2.237 mmol), 3-bromopropylamine hydrobromide(0.979 g, 4.474 mmol), and potassium carbonate (4.0 g) in THF/water (100mL/10 mL) were stirred at room temperature for 1 h. Then most of thesolvent was evaporated at reduced pressure. The residue was partitionedbetween dichloromethane and water (100 mL and 100 mL). Thedichloromethane layer was separated, washed with ice-cold 0.5 N NaOH(2×50 mL) and dried (sodium sulfate). Evaporation of the solvent gavethe product as a single product (0.98 g, 100%) as a white powder andconfirmed by ¹H-NMR.

b)1,2,3,6-Tetrahydro-1-{N-[3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine (44.6 mg, 0.1 mmol),4-(4-fluorophenyl)-4-hydroxypiperidine (28.7 mg, 0.15 mmol), potassiumcarbonate (300 mg), and potassium iodide (30 mg) in THF(10 mL) wasstirred at room temperature for 20 h. The solid material were removed byfiltration, the solvent from the filtrate was evaporated, and theresidue was purified by preparative thin layer chromatography on silicagel using chloroform-methanol-2M ammonia in methanol (100/2/1) as theeluent to afford the product as a viscous oil which was converted to theHCl salt by treatment with 1N HCl in ether; m.p. 160-164° C.; Anal.Calcd. for C₂₉H₂₉N₄O₅F₃.1HCl.0.8Et₂O: C, 57.27; H, 5.85; N, 8.56. Found:C, 57.31; H; 5.75; N, 8.79.

EXAMPLE 38

a)(−)-5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-methoxy-carbonyl]pyrimidine.

To a well stirred solution of(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine(0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol)in CH₂Cl₂ (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) atroom temperature. The solvent was removed in vacuo and the residue waspurified by column chromatography on silica gel with 3:1 Petroleumether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of(−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxy-carbonyl]pyrimidineas a colorless oil.

b)(−)-1,2,3,6-Tetrahydro-4-ethyl-2-oxo-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylicacid.

To a solution of(−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine(0.45 g, 1.18 mmol) in 20 mL of MeOH was added 0.05 g of 10% Pd oncarbon and the resulting suspension was hydrogenated under 100 psi for12 h. The catalyst was then filtered through a pad of celite and waswashed thoroughly with MeOH. All the MeOH washings were collected andthe solvent was removed in vacuo to obtain 0.42 g (99% yield) of(−)-1,2,3,6-tetrahydro-4-ethyl-2-oxo-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylicacid as a white solid which was used in the next reaction withoutfurther purification.

c)(−)1,2,3,6-Tetrahydro-5-{N-[3-(4-methoxycarbonyl)-4-phenyl-piperidin-1-yl]propyl}-carboxamido-1-methoxycarbonyl-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.

To a solution of(−)-1,2,3,6-tetrahydro-4-ethyl-2-oxo-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylicacid (1.18 mmol, 0.4 g) and3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (1.23 mmol, 0.34g) in 20 mL CH₂Cl₂ was added 4-(N,N-dimethylamino)-pyridine (1.16 mmol,0.15 g), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.84mmol, 0.54 g) and the resulting solution was stirred at room temperatureunder argon for 2 days. The solution was then transferred into aseparatory funnel, extracted with CH₂Cl₂, washed with sat. NH₄Clsolution (2×20 mL) and then with brine (20 mL). The organic layer wasseparated and dried over Na₂SO₄, filtered and the solvent was evaporatedin vacuo to obtain an off-white solid. It was purified by columnchromatography on silica gel with 10% MeOH in EtOAc as the solventsystem to obtain(−)1,2,3,6-tetrahydro-5-{N-[3-(4-methoxycarbonyl)-4-phenyl-piperidin-1-yl]propyl}-carboxamido-1-methoxycarbonyl-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidineas a white solid (0.55 g, 79% yield). M.P. 53-55° C.; [α]_(D)=−48.5(c=0.43, CHCl₃). It was characterized as HCl salt. Anal. Calcd. ForC₃₁H₃₇N₄O₆F₂Cl.0.4 CHCl₃: C, 55.23; H, 5.52; N, 8.20. Found: C, 55.29;H, 5.35; N, 7.99.

EXAMPLE 39

(+)-1-3-{[4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylicacid methyl ester.

a)(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine.

To a well stirred solution of(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added asolution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0° C.and the solution was allowed to attain room temperature over 1.5 h. Thesolvent was removed in vacuo and the residue was again dissolved inCHCl₃ (20 mL) and washed with brine. The organic layer was separated,dried over Na₂SO₄, filtered and the solvent was removed in vacuo to get0.81 g of(+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a yellow foam. It was used in the next stepwithout any purification.

b)(+)-4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-cyclopentapyrimidine-3-carboxylicacid-4-nitrophenyl eater.

(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.5 mmol, 0.81 g) was heated in oil bath for 3 h(bath temperature 130° C.). The brown residue thus obtained was washedwith CHCl₃ and(+)-4-(3,4-difluoro-phenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-cyclopentapyrimidine-3-carboxylic acid-4-nitrophenyl ester was obtained as a palebrown solid which was used in the next step without further purification(crude wt. 0.51 g).

c)(+)-1-3-{[4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylicacid methyl ester.

A solution of(+)-4-(3,4-difluorophenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-cyclopentapyrimidine-3-carboxylic acid-4-nitrophenyl ester ((0.30 mmol, 0.13 g)and 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.32 mmol,0.09 g) in 10 mL of anhydrous THF was stirred overnight at roomtemperature. The solvent was removed in vacuo and the residue waspurified by column chromatography (CH₂Cl₂ followed by 9:1 CH₂Cl₂/MeOH)to obtain(+)-1-3-{[4-(3,4-difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylicacid methyl ester as a pale yellow solid (0.12 g, 70%). [α]_(D)=128.1(c=0.525, CHCl₃). It was characterized as HCl salt. M.P. 142-145° C.;Anal. Calcd. For C₂₉H₃₁N₄O₆F₂Cl.0.23 CHCl₃: C, 55.55; H, 4.98; N, 8.87.Found: C, 55.25; H. 5.03; N, 8.52.

EXAMPLE 40

(−)-1-3-{[4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylicacid methyl ester. In a similar way,(−)-1-3-{[4-(3,4-difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylicacid methyl ester was prepared starting with(−)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (overall yield 27%). M.P. 162-165° C. [α]_(D)=−121.3(c=0.52, CHCl₃)

EXAMPLE 41

(+)-1,2,3,6-Tetrahydro -1-{N-[14-(2-carboxamidophenyl)piperazin-1yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine

a)1-(2-Carboxamidophenyl)piperazine Concentrated sulfuric acid (15 mL)was added to 1-(2-cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in around bottom flask and the resulting slurry was stirred at roomtemperature for 48 h. The reaction mixture was poured on crushed icevery slowly and then basified (pH 9) with 50% solution of NaOH. Theaqueous layer was extracted several times with EtOAc, dried over K₂CO₃,filtered and the solvent was evaporated.1-(2-carboxamidophenyl)piperazine was obtained as an off-white solid(1.2 g, 73%). It was used in the next step without further purification.Mass spectrum 206 (M+1, 100%); Combustion analysis was obtained on itshydrochloride salt. Anal. Calcd. for C₁₁H₁₇N₃OCl.0.3 CHCl₃: C, 43.23; H,5.55; N, 13.30. Found: C, 43.58; H, 5.70; N, 12.79.

b) (+)-1,2,3,6-Tetrahydro-1-{N-[4-(2-carboxamidophenyl)piperazin-1yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.

To a solution of(+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine(0.435 g, 1.0 mmol) and 1-(2-carboxamidophenyl)piperazine (0.4 g, 2.0mmol) in 25 mL of anhydrous acetone was added powdered K₂CO₃ (0.69 g,5.0 mmol) and KI (0.17 g, 1.0 mmol) and the resulting suspension washeated to reflux for 10 h. TLC indicated complete formation of theproduct (R_(f)=0.4, 3:0.5 EtOAc/MeOH). The solvent was evaporated andthe residue was dissolved in water (10 mL). The aqueous layer wasextracted in EtOAc (3×30 mL), the separated organic extract was driedover Na₂SO₄ and the solvent was removed in vacuo. The residue thusobtained was purified by column chromatography on silica gel withEtOAc/MeOH (5:1) as the eluting system.(+)-1,2,3,6-tetrahydro-1-{N-[4-(2-carboxamidophenyl)piperazin-1yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidinewas obtained as light yellow powder (0.48 g, 84% yield). The product wasanalyzed as its dihydrochloride salt. M.P. 190-193 ° C.; [α]_(D)=98.8(c=0.31, MeOH); Anal calcd. for C₂₈H₃₄N₆F₂O₅Cl₂.0.35 EtOAc: C, 52.16; H,5.50; N, 12.46. Found: C, 51.84; H, 5.67; N, 12.05.

EXAMPLE 42

1,2,3,6-Tetrahydro-l{N-[4-(N-benzimidazolyl)-piperidin-1-yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.

To a solution of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine(43 mg, 0.1 mmol) in 10 mL of anhydrous acetone was added4-(N-benzimidazolyl)-piperidine (32.6 mg, 0.15 mmol) followed by NaHCO₃(41 mg, 0.3 mmol) and KI (16 mg, 0.1 mmol). The resulting suspension washeated to reflux for 10 h and then cooled to room temperature. Thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography on silica gel with EtOAc followed by 10% MeOH inEtOAc to obtain1,2,3,6-tetrahydro-1{N-[4-(N-benzimidazolyl)-piperidin-1-yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidineas an oil (15 mg, 26% yield). The product thus obtained was thendissolved in 2 mL of chloroform and 0.5 mL of HCl in Et₂O (1 M) wasadded at room temperature. The solvent was removed in vacuo and the HClsalt was characterized by combustion analysis. M.P. 168-172° C. Analcalcd. for C₂₉H₃₃N₆F₂O₅Cl:0.75 CHCl₃: C, 50.43; H, 4.90; N, 11.86.Found: C, 50.84; H, 5.44; N, 11.46.

EXAMPLE 43

(−)-6-(Benzo[1,2,5]oxadiazol-5-yl)-1-carboxamido-4-ethyl-5-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydro pyrimidine.

a) 5-Methylbenzfuroxan.

4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturatedalcoholic sodium hydroxide solution (1.50 1). To this suspension wasadded with cooling (5° C.) commercial aqueous sodium hypochlorite untilthe red color disappeared. The fluffy yellow precipitate formed wasfiltered, washed with cold water and recrystallized from ethanol to get5-methylbenzfuroxan (88.2 g, 89% yield) as a pale solid.

b) 5-Methylbenzofurazan.

To 5-methylbenzfuroxan (88.2 g, 0.59 mol) in refluxing EtOH (75 ml) wasadded dropwise P(OEt)₃ (150 ml). When addition was complete, refluxingwas continued for 1 more hour. The solvent was removed by rotaryevaporation and the residue shaken with water (200 ml) and allowed tostand overnight at (0-5° C.). The brown solid so obtained was filtered ,washed with water and chromatographed on silica gel to yield5-methylbenzofurazan (70 g, 87%) as white needles.

c) 5-Dibromomethylbenzofurazan.

5-Methylbenzofurazan (70 g, 0.52 mol), NBS (325 g), and benzoyl peroxide(0.5 g) were refluxed with stirring in carbon tetrachloride (1.5 1) withexclusion of moisture 5 for 2 days. The reaction mixture was washed withwater (2×0.5 l), brine, dried (Na₂SO₄), and the solvent removed invacuo. The residue was chromatographed on silica (hexane/EtOAc=150/1) toget 122 g (80%) of the title compound as a pink solid.5-Tribromomethylbenzofurazan (17 g, 9%) was also isolated as a pinksolid.

d) 5-Formylbenzofurazan.

To a refluxing mixture of 5-dibromo methylbenzofurazan (122 g, 418 mmol)in EtOH (1 l) was added AgNO₃ (163 g) in 2 l of water. When addition wascomplete, refluxing was continued for 2 hours. The mixture was cooledand the AgBr formed was removed by filtration. The resulting solutionwas concentrated to a small volume and extracted with toluene (10×300ml). The extract was concentrated and the residue collected waschromatographed on silica gel (3 kg), (EtOAc/hexane=8/1000) to get thetitle compound (48.2 g, 78%) as a white solid.

e) 2-Cyanoethyl 3-benzo[1,2,5]oxadiazol-5-yl-2-propionyl-acrylate.

A mixture of 5-formylbenzofurazan (25.0 g, 168.8 mmol), 2-cyanoethyl3-oxo-pentanoate (31.4 g, 203 mmol), and piperidinium acetate (1.22 g,8.40 mmol) in benzene (1.5 l) was refluxed with a Dean-Stark trap for 24hours. Benzene was evaporated, and the residue was chromatographed onsilica (200 g) (EtOAc/CHCl₃=5/100) to get the title compound (32.36,62.1% yield) as a orange oil.

f)2-Cyanoethyl6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimldine-5-carboxylate.

A mixture of 2-cyano-ethyl3-benzo[1,2,5]oxadiazol-5-yl-2-propionyl-acrylate (19 g, 63.48 mmol),O-methylisourea hydrogen sulfate (15.3 g, 88.9 mmol), and4-dimethylaminopyridine (21.3 g, 175 mmol) in THF (200 ml) was stirredat 65° C. for 6 hours. The solvent was evaporated and the residue waschromatographed on silica gel (˜300 g) (hexane/EtOAc=2/1) to get 8 g ofthe title compound as an orange oily solid. This reaction was repeatedfor many times and the yields were between 5% and 38%.

g)6-Benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylicacid 5-(2-cyan-ethyl) eater 1-(4-nitro-phenyl) ester.

To a solution of 2-cyanoethyl 6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate(3.62 g, 10.19 mmol) and 4-dimethylaminopyridine (1.49 g, 12.2 mmol) inCH₂Cl₂ (75 ml), at 0° C., was added 4-nitrophenylchloroformate (2.46 g,12.22 mmol). The reaction mixture was slowly warmed to r.t. at which itwas stirred for 20 hours. Then, the solvent was evaporated and theresidue was purified by flash column chromatography (˜60 g of SiO₂,CHCl₃/EtOAc=100/3) to get the title compound (1.96 g, 37% yield) as ayellow solid.

h)2-Cyanoethyl ester6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1-(1-phenyl-ethylcarbamoyl)-1,6-dihydro-pyrimidine-5-carboxylate.

A solution of6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylicacid 5-(2-cyanoethyl) ester 1-(4-nitrophenyl) ester (2.2 g, 4.22 mmol )and (R)-(+)-α- methylbenzylamine (1.36 ml, 10.6 mmol) in CH₂Cl₂ (30 ml)was stirred at room temperature for 10 hours. The solvent wasevaporated, and the residue was chromatographed on silica gel (100 g)(CHCl₃ /EtOAc=30/1) to get the two diasteromers of the title compound(1.03 g in total, 49%).

i) (−)-2-Cyanoethyl6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate.

A mixture of (−)-2-cyanoethyl ester6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1-(1-phenyl- ethylcarbamoyl)-1,6-dihydro-pyrimidine-5-carboxylate (557 mg, 1.11 mmol) and1,8-diazabicyclo[5,4,0]undec-7-ene (82.5 ml, 0.55 mmol) in benzene (15ml) was stirred at 50° C. for 1 hour. The solvent was evaporated, andthe residue was chromatographed on silica gel (˜30 g) (CHCl₃/EtOAc/2 NNH₃ in MeOH=40/10/1) to get the title compound (270 mg, 68.5% yield) asa yellow solid. No rotation was observed for this compound.

j)(−)-6-Benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylicacid 5-(2-cyanoethyl) ester 1-(4-nitro-phenyl) ester.

To a solution of (−)-2-cyanoethyl6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate(220 mg, 0.62 mmol) and 4-dimethylaminopyridine (99 mg, 0.81 mmol) inCH₂Cl₂ (12 ml), at 0° C., was added 4-nitrophenylchloroformate (164 mg,0.81 mmol). The reaction mixture was slowly warmed to r.t. at which itwas stirred for 24 hours. The solvent was evaporated and the residue waspurified by flash column chromatography (˜30 g of SiO₂,CHCl₃/EtOAc=38/1) to get the title compound (301 mg, 93% yield) as ayellow solid.

k)(−)-6-(Benzo[1,2,5]oxadiazol-5-yl)-1-carboxamido-4-ethyl-5-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1,6-dihydropyrimidine.

To(−)-6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylicacid 5-(2-cyanoethyl) ester l-(4-nitrophenyl) ester (100 mg, 0.19 mmol)in dry THF (10 ml) ammonia (gas) was introduced with a balloon at roomtemperature. It was stirred at room temperature for 14 hours. TLC and ¹HNMR of the reaction mixture showed that the reaction was complete. NaOH(1 N, 3 ml) was added at room temperature. After it was stirred for 6hours, HCl solution (6 N, 4 ml) was added. It was stirred at roomtemperature for 14 hours. The solvent was evaporated to get a whitesolid which was used directly in the next step.

A mixture of the crude product from the above step, 4-dimethylaminopyridine (61mg, 0.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5mmol) in CH₂Cl₂ (15 ml) was stirred at room temperature for 4 hours.Methyl 1-(3-amino-propyl)-4-phenyl-piperidine-4-carboxylate (140 mg, 0.5mmol) was added. The reaction mixture was stirred at room temperaturefor 16 hours. The solvent was evaporated and the residue waschromatographed on silica gel (5 g) (CHCl₃/MeOH/2 N NH₃ in MeH=250/2/1)to get the title compound as a white solid (10.8 mg, 10% yield over 3steps). [α]_(D)=−303.9. Hydrochloride of the title compound was madewith HCl in ether. M.P. of the salt: 140-143° C. Calculated forC₃₀H₃₅N₇O₆+1.0HCl+0.6 ether: C, 58.03%; H, 6.31%; N, 14.62%. Found: C,58.07%; H, 6.08%; N,14.66%.

EXAMPLE 44

6-(3,4-Difluoro-phenyl)-1-[3-(3′,6′-dihydro-[2,4′]bipyridinyl-1′-yl)-propylcarbamoyl]-4-methyl-5-methoxycarbonyl-2-oxo-1,2,3,6-tetrahydropyrimidinehydrochloride.

a) 1-(3-Aminopropyl)-4-[pyrid-2-yl]pyridinium bromide hydrobromide.

A solution of 2,4′-dipyridyl (5.0 g, 32.0 mmol) and 3-bromopropylaminehydrobromide (7.0 g, 32.0 mmol) in DMF (50.0 mL) and acetonitrile (50.0mL) was heated at 90-95° C. for 1 h. After cooling, the white solid thatcame out was filtered, washed with Et₂O and dried. The mother liquor wasconcentrated to remove Et₂O and then heated to 90-95° C. for 4 h. Thesolvent was evaporated and the white residue was triturated with Et₂O(100.0 mL) and filtered. The combined weight of the salt was 11.6 g(97%).

b) 3-(3′,6′-Dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine.

To a solution of 1-(3-aminopropyl)-4-[pyrid-2-yl]pyridinium bromidehydrobromide (0.66 g, 1.75 mmol) in 20.0 mL MeOH was added NaBH₄ (0.101g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30min and then quenched with 6M HCl solution. The solution wasconcentrated to 20.0 mL and basified with 50% NaOH solution to pH 12.Extracted with CHCl₃ (5×30.0 mL), dried over MgSO₄ and the solvent wasremoved to give3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine as an oil(0.37 g, 96% yield). It is used in the next step immediately withoutpurification.

c)6-(3,4-Difluoro-phenyl)-1-[3-(3′,6′-dihydro-[2,4′]bipyridinyl-1′-yl)-propylcarbamoyl]-4-methyl-5-methoxycarbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidinehydrochloride.

A solution of6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine(20 mg, 0.045 mmol) and 3-(3′,6′-dihydro-2′H-[2,4′]bipyridyl-1-yl)propylamine (9.7 mg, 0.045 mmol) inCH₂Cl₂ (10 ml) was stirred at room temperature for 3 days. The solventwas removed in vacuum. The residue was separated on preparative TLC(CHCl₃/MeOH=100/15) to get the title compound (21mg, 89% yield) as ayellow solid. Hydrochloride salt was made with HCl in ether. M.P. of thesalt: 242-244° C. Calcd for C₂₇H₂₉N₅O₄F₂+2.0 HCl+1.05 CHCl₃+1.05 ether:C, 48.32%; H, 5.35%; N, 8.74%. Found: C, 48.10%; H, 5.13%; N, 8.72%.

EXAMPLE 45

6-(3,4-Difluorophenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-4-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acidmethyl ester.

A solution of6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine(100 mg, 0.22 mmol) and 1-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) inCH₂Cl₂ (10 ml) was stirred at room temperature for 3 hours. The solventwas removed in vacuum. The residue was separated on preparative TLC(CHCl₃/MeOH=100/15) to get the title compound (80 mg, 84% yield) as awhite solid. Hydrochloride of title compound was made with HCl in ether.Calcd for C₂₀H₂₁N₅O₄F₂+0.3 H₂O: C, 54.74%; H, 4.99%; N, 15.89%. Found:C, 54.92%;H, 4.65%; N, 15.77%. M.P. of the salt: 221-224° C.

EXAMPLE 46

6-(3,4-Difluorophenyl)-1-{N-[3-(2-phenylimidazol-1-yl)propyl]}carboxamido-4-methyl-5-methoxycarbonyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride.

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine (100 mg, 0.22 mmol), 2-phenylimidazole (32.3 mg,0.22 mmol), and CsCO₃ (358 mg, 1.1 mmol) in DMF (10 ml) was stirred atroom temperature for 2 days. The solid was filtered out. The solutionwas concentrated and separated on preparative TLC (EtOAc/hexane=3/1) toget the title compound (41 mg, 37% yield) as a white oily solid.Hydrochloride of title compound was made with HCl in ether. M.P. of thesalt: 278-282° C. Calculated for C₂₆H₂₅N₅O₄F₂+2.0 HCl+0.25 H₂O: C,52.23%; H, 4.60%; N, 11.60%. Found: C, 52.21%; H, 4.69%; N, 11.11%.

EXAMPLE 47 AND EXAMPLE 48

(+)-, and(−)-3,6-Dihydro-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methyl pyrimidinedihydrochloride.

a) 4Methyl 2-acetyl-3-(3,4,5-trifluoro-phenyl)-acrylate.

A mixture of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol), methylacetoacetate (0.81 ml, 7.5 mmol), and piperidinium acetate (45 mg, 0.31mmol) in benzene (10 ml) was refluxed with a Dean-Stark trap for 12hours. The solvent was evaporated, and the residue was chromatographedon silica gel (˜50 g) (EtOAc/hexane=1/6) to get the title compound (825mg, 51% yield) as a mixture of cis and trans isomers (yellow oil).

b) Methyl2-methoxy-4-methyl-6-(3,4,5-trifluoro-phenyl)-1,6-dihydro-pyrimidine-5-carboxylate.

A mixture of methyl 2-acetyl-3-(3,4,5-trifluoro-phenyl)-acrylate (670mg, 2.60 mmol), O-methylisourea hydrogen hemisulfate (448 mg, 3.63mmol), and 4-dimethylaminopyridine (407 mg, 3.63 mmol) in ethanol (20ml) was stirred at 65° C. for 2 days. The solid formed was filtered out.The filtrate was concentrated and chromatographed on silica gel (30 g)(CH₂Cl₂/EtOAc=9/1) to get the title compound (390 mg, 48% yield) as apale yellow oil. Calculated for C₁₄H₁₃N₂O₃F₃; C, 53.50%; H, 4.20%; N,8.90%. Found: C, 53.24%; H, 4.20%; N, 8.60%.

c) 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-(4-nitrophenyloxy)carbonyl -6-(3,4,5-trifluorophenyl) -pyrimidine.

To a solution of methyl1,6-dihydro-2-methoxy-4-methyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine-5-carboxylate(385 mg, 1.23 mmol) and 4-dimethylaminopyridine (195 mg, 1.60 mmol) inCH₂Cl₂ (15 ml), at room temperature, was added 4-nitrophenylchloroformate (322 mg, 1.60 mmol). The reaction solution was stirred atroom temperature for 2 days. The white solid formed was filtered out.The filtrate was concentrated and chromatographed on silica gel (˜20 g)(CHCl₃/CH₃OH=9/1) to get the titled compound (206 mg, 35% yield) as awhite solid. Calculated for C₂₁H₁₆N₃O₇F₃+1.0 H₂O: C, 50.71%; H, 3.65%;N, 8.45%. Found: C, 50.83%; H, 3.29%; N, 8.33%.

d)1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of 1,6-dihydro-5-methoxycarbonyl -2-methoxy-(4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-4-methyl-pyrimidine (25 mg, 0.05mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]-propylamine (16 mg, 0.078mmol) was stirred at room temperature for 12 hours. The solvent wasevaporated and the residue chromatographed on silica gel (˜5 g)(CHCl₃/EtOAc=30/1 ) to get the title compound (16 mg, 57% yield) as apale solid.

e)1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidinedihydrochloride.

1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidinefrom the previous step was dissolved in CH₂Cl₂ (5 ml) and concentratedHCl solution (0.5 ml) was added. The reaction mixture was stirred atroom temperature for 1 hour. NaOH solution (1 N) was added toneutralized the reaction mixture. It was extracted with CH₂Cl₂. Theextractant was dried (Na₂SO₄) and concentrated to get the title compound(16 mg, quantitative) as a pale solid. Hydrochloride of the titlecompound was made with HCl in ether. Calculated for C₂₇H₂₉N₅O₄F₃+2.0HCl+4.0 THF+0.8 CH₂Cl₂: C, 54.02%; H, 6.69%; N. 7.19%. Found: C, 54.00%;H, 6.48%; N, 7.42%.

f) (+)-, and(−)-3,6-Dihydro-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methyl pyrimidinedihydrochloride.

The enantiomers were separated by chiral HPLC separation (column:chiralpak AS) of the racemic1,2,3,6-tetrahydro-1-{N-[4-(2-pyridyl)-piperidine-1-yl]propyl}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methylpyrimidine dihydrochloride which wassynthesized in the previous step. The (+) isomer: [α]_(D)=+80.4 (c=0.2 gin 100 ml dichloromethane): The (−) isomer: [α]_(D)=−82.2. Hydrochloridesalts of the title compounds was made with HCl in ether.

EXAMPLE 49

(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidinedihydrochloride.

a) Methyl 2-methoxyacetyl-3-(3,4,5-trifluoro-phenyl)-acrylate.

A mixture of 3,4,5-trifluoro benzaldehyde (10 g, 62.5 mmol), methyl4-methoxyacetoacetate (9.7 ml, 75.0 mmol), and piperidinium acetate (450mg, 3.1 mmol) in benzene (100 ml) was refluxed with a Dean-Stark trapfor 8 hours. The white solid formed (some side product) was filteredout. The solvent was evaporated, and the residue was chromatographed onsilica gel (˜1 Kg) (toluene/t-butyl methyl ether=8/1) to get the titlecompound (4.5 g, 25% yield) as a mixture of cis and trans isomers (whitesolid).

b)1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of methyl 2-methoxyacetyl-3-(3,4,5-trifluoro-phenyl)-acrylate(6.0 g, 20.8 mmol), O-methylisourea hydrogen hemisulfate (3.6 g, 29.2mmol), and 4-dimethylaminopyridine (3.6 g, 29.2 mmol) in ethanol (20 ml)was stirred at 65° C. for 12 hours. The solid formed was filtered out.The filtrate was concentrated and chromatographed on silica gel (˜1 kg)(hexane/ether=2/1) to get the title compound (4.0 g, 56% yield) as apale colorless oily solid.

c)1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-pyrimidine.

To a solution of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine(3.24 g, 9.41 mmol) and 4-dimethylaminopyridine (1.38 g, 11.3 mmol) inCH₂Cl₂ (20 ml), at room temperature, was added 4-nitrophenylchloroformate (2.28 g, 11.3 mmol). The reaction solution was stirred atroom temperature for 2 days. The white solid formed was filtered out.The filtrate was concentrated and chromatographed on silica gel(hexane/ether=1/1) to get the title compound (3.70 g, 77% yield) as ayellow solid.

d)(+)-, and(−)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-[N-(2-methylbenzyl)]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-pyrimidine(3.80 g, 7.46 mmol) and (R)-(+)-α-methylbenzylamine (2.02 mg, 16.4 mmol)in CH₂Cl₂ was stirred at room temperature for 2 days. The solvent wasevaporated and the residue chromatographed on silica gel(toluene/t-butyl methyl ether=5/1) to get the title compound as yellowoil solids. For the less polar isomer (1.81 g, 50% yield):[α]_(D)=+164.3. For the more polar isomer (1.79 g, 50% yield):[α]_(D)=−86.2.

e)(+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of(+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-[N-(2-methylbenzyl)]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (1.81 g 3.81 mmol) and1,8-diazabicyclo[5,4,0]undec-7-ene (0.28 ml, 1.90 mmol) in benzene (10ml) was stirred at room temperature for 4 days. The solvent wasevaporated, and the residue was chromatographed on silica gel (˜500 g)(hexane/ether=2.5/1) to get the title compound (1.2 g, 91% yield) as ayellow oil. No rotation was observed for this compound.

f)(+)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl -6-(3,4,5-trifluorophenyl)-pyrimidine.

To a solution of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine(1.20 g, 3.49 mmol) and 4-dimethylaminopyridine (0.51 g, 4.18 mmol) inCH₂Cl₂ (20 ml), at room temperature, was added 4-nitrophenylchloroformate (0.84 g, 11.3 mmol). The reaction solution was stirred atroom temperature for 12 hours. The white solid formed was filtered out.Trials to purify the crude product on silica gel only hydrolyzed thedesired product to the start materials. The crude product was used inthe next step without any further purification.

g)(+)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of (+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-pyrimidine and3-[4-(2-pyridyl)-piperidin-1-yl]-propylamine (215 mg, 1.05 mmol) wasstirred at room temperature for 12 hours. The solvent was evaporated andthe residue chromatographed on prep. TLC (CHCl₃/MeOH=100/15) to get thetitle compound (115 mg, 22% yield over 2 steps) as a yellow oil.

h) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidinedihydrochloride.

1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidinefrom the previous step was dissolved in CH₂Cl₂ (5 ml) and HCl solution(6 N,0.5 ml) was added. The reaction mixture was stirred at roomtemperature for 4 hour. KOH solution (1 N) was added to neutralize thereaction mixture. It was extracted with CH₂Cl₂. The extractant was dried(Na₂SO₄) and concentrated to get the title compound (106 mg, 94% yield)as a pale oily solid. [α]_(D)=+78.6 (c=0.5 g in 100 ml dichloromethane)Hydrochloride of the title compound was made with HCl in ether.Calculated for C₂₈H₃₂N₅O₅F₃+3.8 HCl+1.8 EtOAc: C, 48.44%; H, 5.80%; N,8.02%. Found: C, 48.19%; H, 5.38%; N, 8.32%.

EXAMPLE 50

(−)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidinedihydrochloride.

a)(−)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of(−)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-[N-(2-methylbenzyl)]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine(1.79 g, 3.80 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (0.28 ml,1.90 mmol) in benzene (10 ml) was stirred at room temperature for 4days. The solvent was evaporated, and the residue was chromatographed onsilica gel (˜500 g) (hexane/ether=2.5/1) to get the title compound (0.92g,70%) as a yellow oil. No rotation was observed for this compound.

b) (−)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl -6-(3,4,5-trifluorophenyl)-pyrimidine.

To a solution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl -6-(3,4,5-trifluoro-phenyl)-pyrimidine (0.92 g, 2.67mmol) and 4-dimethylaminopyridine (0.46 g, 3.74 mmol) in CH₂Cl₂ (20 ml),at room temperature, was added 4-nitrophenyl chloroformate (0.75 g, 3.74mmol). The reaction solution was stirred at room temperature for 2 days.The white solid formed was filtered out. The filtrate 4 was concentratedand chromatographed on silica gel (hexane/ether=3/1) to get the titlecompound (1.01 g, 79% yield) as a yellow solid.

c)(−)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluorophenyl)-pyrimidine.

A mixture of(−)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-pyrimidine(300 mg, 0.59 mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]-propylamine(160 mg, 0.77 mmol) was stirred at room temperature for 12 hours. Thesolvent was evaporated and the residue chromatographed on prep. TLC(CHCl₃/MeOH/2 N NH₃ in MeOH=20/2/1) to get the title compound (290 mg,83% yield) as a yellow oil.

d)(−)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidinedihydrochloride.

(−)1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine(290 mg, 0.49 mmol) was dissolved in CH₂Cl₂ (5 ml) and 9 HCl solution (6N, 2 ml) was added. The reaction mixture was stirred at room temperaturefor 10 hour. KOH solution (1 N) was added to neutralized the reactionmixture. It was extracted with CH₂Cl₂. The extractant was dried (Na₂SO₄)and concentrated to get the title compound (180 mg, 64% yield) as a paleoily solid.[α]_(D)=−31.4 (c=0.44 g in 100 ml dichloromethane).Hydrochloride of the title compound was made with HCl in ether.Calculated for C₂₈H₃₂N₅O₅F₃+2.0 HCl+0.8 ether+0.8 CH₂Cl₂: C, 50.59%; H,5.78%; N, 9.22%. Found: C, 50.86%; H, 5.82%; N, 8.75%.

EXAMPLE 51

1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxamido-6-(2,4,5-trifluorophenyl- pyrimidinedihydrochloride.

a) Methyl 2-acetyl-3-(2,4,5-trifluoro-phenyl)-acrylate.

A mixture of 2,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol), methylacetoacetate (0.81 ml, 7.4 mmol), and piperidinium acetate(38 mg, 0.26mmol) in benzene (10 ml) was stirred at room temperature for 2 days. Thesolvent was evaporated, and the residue was chromatographed on silicagel (˜50 g) (hexane/ether=5/1) to get the title compound (1.60 g,quantitative ) as a mixture of cis and trans isomers (colorless oil).

b)1,6-Dihydro-2-methoxy-5—methoxycarbonyl-4-methyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of methyl 2-acetyl-3-(2,4,5-trifluoro-phenyl)-acrylate (1.60g, 6.20 mmol), O-methylisourea hydrogen hemisulfate (1.07 g, 8.68 mmol),and 4-dimethylaminopyridine (1.06 g, 8.68 mmol) in ethanol (10 ml) wasstirred at 65° C. for 2 days. The solid formed was filtered out. Thefiltrate was concentrated and chromatographed on silica gel (˜50 g)(CH₂Cl₂/EtOAc=9/1) to get the title compound (982 mg, 50% yield) as apale colorless oily solid.

c) 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-(4-nitrophenyloxy) carbonyl -6-(2,4,5-trifluorophenyl) -pyrimidine.

To a solution of1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine(600 mg, 1.91 mmol) and 4-dimethylaminopyridine (280 mg, 2.29 mmol) inCH₂Cl₂ (8 ml), at room temperature, was added 4-nitrophenylchloroformate (462 mg, 2.29 mmol). The reaction solution was stirred atroom temperature for 18 hours. The white solid formed was filtered out.The filtrate was concentrated and chromatographed on silica gel (˜50 g)(hexane/ether=4/1) to get the title compound (143 mg, 16 t yield) as awhite solid.

d)1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of116-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-(4-nitrophenyloxy)carbonyl-6-(2,4,5-trifluorophenyl)-pyrimidine(70 mg, 0.146 mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (46mg, 0.220 mmol) was stirred at room temperature for 12 hours. Thesolvent was evaporated and the residue separated on preparative TLC(CHCl₃/MeOH/2 N NH₃ in MeOH=20/2/1) to get the title compound (59 mg,72% yield ) as a yellow oil.

e)1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl]- propyl}carboxamido-6-(2,4,5-trifluorophenyl-pyrimidine dihydrochloride.

1,6-Dihydro-2-methoxy-5methoxycarbonyl-4-methyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine(59 mg, 0.11 mmol) was dissolved in THF (3 ml) and HCl solution (6 N, 2ml) was added. The reaction mixture was stirred at room temperature for6 hour. KOH solution (1 N) was added to neutralized the reactionmixture. It was extracted with CH₂Cl₂. The extractant was dried (Na₂SO₄)and concentrated to get the title compound (50 mg, 87% yield) as a whitesolid. Hydrochloride of the title compound was made with HCl in ether.Calculated for C₂₇H₃₀N₅O₄F₂+2.0 HCl+1.0 C₆H₁₂+1.0 CHCl₃ C, 49.68%; H,5.52%; N, 8.52%. Found: C, 49.22%; H, 6.11%; N, 8.59%. M.P. of the salt:239-243° C.

EXAMPLE 52

4-(3,4-Difluorophenyl)-3-[3-(3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]oct-8-yl)propylcarbamoyl]-6-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester

a) 8-Benzyl-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol:

N-benzyltropinone (14.4 g, 66.7 mmol) was added dropwise (neat) to asolution of phenyl magnesium bromide (100 mL, 0.1 M in THF). Theaddition was continued as such a rate to maintain a gentle reflux. Oncethe addition was complete, the reaction mixture was heated at refluxtemperature for 19 hours, cooled to room temperature, poured over 200 mLof crushed ice, saturated with ammonium chloride, and extracted with3×100 mL of ethyl acetate. The combined organic extracts were dried(K₂CO₃), solvent removed in Vacuo, and the crude product waschromatographed on 500 g of silica packed with CHCl₃. The column waseluted with CHCl₃ (1 L), 5%EtOAc—CHCl₃ (1 L), 10% (1 L), 20%, (1 L), 30%(1 L), 50% (1 L), 100% EtOAc (1 L), and 10% MeOH-EtOAc (2 L), to give11.8 g (40%) of the desired product as a slightly yellow oily solid.Anal. Calc. for C₂₀H₂₃N₁O₁: C, 81.87; H, 7.90; N, 4.77. Found: C, 81.63;H, 8.01; N, 4.70.

b) 3-Phenyl-8-azabicyclo[3.2.1]octan-3-ol:

A mixture of 5.10 g of 8-benzyl-3-phenyl-8-azabicyclo [3.2.1]octan-3-ol(17.4 mmol), 3.15 g of 10% Pd/C in 50 mL of 95% ethanol was hydrogenatedin a pressurized bomb (200 psi) at 60-70° C. (bath temperature) for 16hours. The reaction mixture was filtered through a pad *of Celite, andthe solids were washed with 5×30 mL of methanol. The combined organicextracts were concentrated, and the crude product was chromatographed on300 g of silica packed with EtOAc-MeOH-isopropanol (30:2:1). The columnwas eluted with EtOAc-MeOH-isopropanol 25:2:1 (1 L), 20:2:1 (1 L), and15:2:1 (1 L) to give 3.16 g (89%) of the desired product as a slightlyyellow oily solid. Anal. Calc. for C₁₃H₁₇N₁O₁: C, 76.81; H, 8.43; N,6.89. Found: C, 76.57; H, 8.53; N, 6.80.

c)4-(3,4-Difluorophenyl)-3-[3-(3-hydroxy-3-phenyl-8-a zabicyclo[3.2.1]oct-8-yl) propylcarbamoyl]-6-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester.

A mixture of 243 mg of 3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (1.2mmol), 640 mg of 1,2,3,6-tetrahydro-1-{3-bromopropyl}carboxamido-5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo pyrimidine (1.44 mmol),197 mg of K₂CO₃ (1.44 mmol), catalytic amounts (a few crystals) of KI in10 mL of ethanol were heated at reflux temperature for 4 hours. Thereaction mixture was cooled to room temperature, and the crude productwas purified with preparative TLC (2000 microns, 10% MeOH-EtOAc) to give290 mg (43%) of the desired product as a slightly yellow viscous oil.Anal. Calc. For C₃₀H₃₄F₂N₄O₅+1.0 Methanol: C, 61.99; H, 6.38; N, 9.33.Found: C, 62.12; H, 6.02; N, 9.58. The hydrochloride salt was preparedby dissolving 150 mg of the free base in minimum EtOAc and excess 1N HClin ether was added. The solvent was decanted and the separated oil wastriturated with ether to give the hydrochloride as a slightly yellowpowder: Anal. Calc. for C₃₀H₃₄F₂N₄O₅+1.0 HCl+1.2 H₂O: C, 57.50; H, 6.01;N, 8.94. Found: C, 57.76; H, 5.82; N, 8.50.

EXAMPLE 53 AND EXAMPLE 54

1,2,3,6-Tetrahydro-1-(N-(3-(3-imidazol-1-yl)propyl)amino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidinedihydrochloride and1,2,3,6-Tetrahydro-1-(N-(3-(2-indol-3-yl))ethyl)amino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride

In two separate reaction vessels, a mixture of 89 mg of1,2,3,6-tetrahydro-1-{3-bromopropyl}carboxamido-5-met hoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo pyrimidine (0.200 mmol),0.200 mmol of the following nucleophiles (25.0 mg of1-(3-aminopropyl)imidazole, 25 mg of tryptamine), 89 mg of K₂CO₃, in 1mL of acetonitrile were heated at reflux temperature for 2-5 days,applied to the preparative-TLC and eluted with CHCl₃—MeOH—2N NH₃ in MeOH(10:1:1) to give the title compounds. The hydrochlorides were preparedby dissolving the title compounds in minimum EtOAc, and excess 1N HCl inether was added until no more precipitate was apparent. The solids werefiltered, washed with ether, and dried under high vacuum.

1,2,3,6-Tetrahydro-1-(N-(3-(3-imidazol-1-yl)propyl) am ino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidinedihydrochloride (12 mg): Anal. Calc. for C₂₃H₂₈F₂N₂O₄+2.0 HCl+0.6ether+0.3 CH₂Cl₂: C, 49.31; H, 5.76; N, 13.12. Found: C, 49.07; H, 5.78;N, 13.28.

1,2,3,6-Tetrahydro-1-(N-(3-(2-indol-3-yl))ethyl)amino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride

(23 mg); Anal. Calc. for C₂₇H₂₉F₂N₅O₄+1.0 HCl +3.7 THF: C, 60.58; H,7.25; N, 8.45. Found: C, 60.84; H, 7.21; N, 8.48.

EXAMPLE 55

6-(3,4-Difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-5-(3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-propylaminocarbonyl)-2,4-dimethylpyrimidine

a) Benzyl 3-oxo-2-(3,4-difluorobenzylidenyl)butanoate.

A mixture of 3,4-difluorobenzaldehyde (7.1 g, 50 mmol.), benzylacetoacetate (12.48 g, 65 mmol.), acetic acid (0.15 g, 2.5 mmol.),piperidine (0.212 g, 2.5 mmol.) and benzene (300 mL) was refluxed undera dean-stark trap overnight. After the removal of solvent, the residuewas then dissolved in ethyl acetate and washed with saturated KHSO₄,saturated NaHCO₃, water and then dried over Na₂SO₄. The solvent wasevaporated, and the residue was flash chromatographed over silica gel(eluent: 1:1 v/v ethyl acetate-hexane) to give the product in 87% yield(13.7 g) as a yellow solid.

b)5-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine.

To a stirred solution of acetamidine hydrochloride (1.42 g, 15 mmol.) inDMF (10 mL) were added a solution of potassium tert-butoxide (1.23 g, 11mmol.) in DMF (10 mL) and a solution of the above yellow solid (3.16 g,10 mmol.) in DMF (10 mL) at 0° C. After the mixture was stirred for 15min at 0° C., p-toluenesulfonic acid monohydrate (3.8 g, 20 mmol.) wasadded. The mixture was heated at 100-110° C. for 2 hrs. After cooling,it was quenched with 2N aqueous NaOH solution and extracted with ether.The organic layer was dried over Na₂SO₄ and evaporated. The residue wasflash chromatographed over silica gel (eluent: 100:5 v/v ethylacetate-2M ammonia in methanol) to give the product in 42% yield (1.5 g)as an off-white solid.

c)5-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-2,4-dimethylpyrimidine.

To a stirred slurry of NaH (59 mg, 60% in mineral oil, 1.47 mmol.) inTHF (5 mL) was added a solution of the above off-white solid (0.5 g, 1.4mmol.) in THF (10 mL) at 0° C. After 5 min, methyl chloroformate (0.16g, 1.7 mmol.) was added at 0° C. Stirring was continued at roomtemperature for 30 min. The mixture was quenched with brine andextracted with ethyl acetate. The organic layer was dried over Na₂SO₄and evaporated to give a quantitative yield of the product as a yellowsolid.

d)5-Carboxy-6-(3,4-difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-2,4-dimethylpyrimidine.

A solution of the above yellow solid (0.63 g, 1.52 mmol) in methonal (20mL) was subjected to hydrogenation with a H₂ balloon in the presence ofpalladium (63 mg, 5% on C). The reaction was carried out at roomtemperature for 30 min. The catalyst was then filtered off and thesolvent was removed in vacuo to give the product in 99% yield (0.487 g)as an off-white solid.

e)6-(3,4-Difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-5-(3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-propylaminocarbonyl)-2,4-dimethylpyrimidine.

A mixture of the above off-white solid (0.070 g, 0.22 mmol.),4-dimethylaminopyridine (0.040 g, 0.33 mmol.),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g,0.30 mmol.) and CH₂Cl₂ (5 mL) was stirred at room temperature for 0.5hr. After the addition of3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.075 g, 0.27mmol.), the mixture was refluxed overnight. To the mixture was addedanother 25 mL of CH₂Cl₂ and washed with saturated NH₄Cl solution. Afterthe removal of the solvent, the residue was flash chromatographed oversilica gel (eluent: 85:15 v/v ethyl acetate-methonal) to give the titlecompound in 42% yield (0.052 g) as a white solid: mp 55-57° C. Anal.Calcd. for C₃₁H₃₆F₂N₄O₅.0.5CH₂Cl₂: C, 60.52; H, 5.97; N, 8.96. Found: C,60.61; H, 6.09; N, 8.94.

EXAMPLE 56

6-(3,4-Difluorophenyl)-1,6-dihydro-5-(3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylaminocarbonyl)-1-methoxymethyl-2,4-dimethylpyrimidine

a)5-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine.

To a stirred slurry of NaH (24 mg, 60% in mineral oil, 0.6 mmol.) in THF(5 mL) was added a solution of5-benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine(0.2 g, 0.56 mmol.) in THF (10 mL) at 0° C. After 10 min, chloromethylmethyl ether (0.043 mL, 0.57 mmol.) was added at 0° C. Stirring wascontinued at room temperature for 3 hrs. The mixture was quenched withbrine and extracted with ethyl acetate. The organic layer was dried overNa₂SO₄ and evaporated to give the product in 44.5% yield as a yellowoil.

b)5-Carboxy-6-(3,4-difluorophenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine.

A solution of the above yellow oil (0.17 g, 0.43 mmol) in methanol (20mL) was subjected to hydrogenation with a H₂ balloon in the presence ofpalladium (34 mg, 5% on C). The reaction was carried out at roomtemperature for 0.5 hr. The catalyst was then filtered off and thesolvent was removed in vacuo to give the product in 100% yield (0.13 g)as an off-white solid.

c)6-(3,4-Difluorophenyl)-1,6-dihydro.-5-(3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylaminocarbonyl)-1-methoxymethyl-2,4-dimethylpyrimidine.

A mixture of5-carboxy-6-(3,4-difluoro-phenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine(0.13 g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g,0.82 mmol.) and CH₂Cl₂ (5 mL) was stirred at room temperature for 0.5hr. After the addition of3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.17 g, 0.62mmol.), the mixture was refluxed overnight. To the mixture was addedanother 25 mL of CH₂Cl₂ and washed with saturated NH₄Cl solution. Afterremoval of the solvent, the residue was flash chramotographed oversilica gel (eluent: 80:20 v/v ethyl acetate- methanol) to give the titlecompound in 32% yield (0.075 g) as a pale yellow solid: mp 53-57° C.Anal. Calcd. for C₃₁H₃₈F₂N₄O₄.0.25CHCl₃: C, 62.71; H, 6.44; N, 9.36.Found: C, 62.62; H, 6.79; N, 9.19.

EXAMPLE 57

1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)pentyl)-4-methyl-6-(4-nitrophenyl)-pyrimidine

a) 1,6-Dihydro-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-pyrimidine.

Sodium (0.55 g, 23.9 mmol) was allowed to react with anhydrous EtOH (100mL). Then the solution was cooled by an ice water bath when formamidineacetate (2.29 g, 22.0 mmol) and methyl2-(4-nitrobenzylidenyl)acetoacetate (5.00 g, 20.1 mmol) were added. Themixture was stirred at room temperature for 3 h. The product wasfiltered off as a yellow powder (4.68 g, 80%). It was mixed withp-toluenesulfonic acid monohydrate (6.7 g, 35.2 mmol) in dry DMSO (125mL) and heated at 110° C. for 3 h. Ice water (450 mL) was added and theproduct as a tosylate was filtered off as an off-white solid (5.55 g,78%).

b)1-(5-Chloropentyl)-1,6-dihydro-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)pyrimidine.

The above solid (2.44 g, 5.45 mmol) was added to dry THF (50 mL)containing sodium hydride (60% oil dispersion, 480 mg, 12.0 mmol) andcooled by an ice water bath. Then 1-bromo-5-chloropentane (3 mL, 22.8mmol) was added. The mixture was stirred at room temperature for 7 hbefore ice water was added. Extraction with EtOAc gave a dark oil (4.455g) which was flash chromatographed over silica gel (120 g) eluting withEtOAc/hexane/Et₃N (15:15:1) to afford a brown oil (1.43 g, 69%).

c) 1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenyl-piperidin-1-yl)pentyl)-4-methyl-6-(4-nitrophenyl)-pyrimidine.

The above oil (220 mg, 0.58 mmol) was mixed with4-methoxy-carbonyl-4-phenylpiperidine (127 mg, 0.58 mmol) and potassiumiodide (106 mg, 0.64 mmol) in dry glyme (4 mL) cooled by an ice waterbath. Then sodium hydride (24 mg, 60% oil dispersion, 0.60 mmol) wasadded. The mixture was heated at reflux overnight and more KI (106 mg)was added. Reflux was continued for two more days. Ice water was added.Extraction with EtOAc (3×3 mL) gave a brown oil (158 mg). It wasdissolved in CHCl₃/EtOAc and flash chromatographed over silica gel (16g) eluting with EtOAc/MeOH/Et₃N (20:1:1) to afford a yellow oil (89 mg,27%). Anal. Calcd. for C₃₁H₃₈N₄O₆.3/4H₂O: C, 64.62; H, 6.91; N, 9.72.Found: C, 64.56; H, 6.84; N, 9.76.

EXAMPLE 58

6-(2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethyl-5-methylaminocarbonyl-pyrimidine

a) Benzyl 3-oxo-2-(2,4-difluorobenzylidenyl)butanoate.

A mixture of 2,4-difluorobenzaldehyde (7.1 g, 50 mmol.), benzylacetoacetate (12.48 g, 65 mmol.), acetic acid (0.15 g, 2.5 mmol.),piperidine (0.212 g, 2.5 mmol.) and 2-propanol (300 mL) was stirred atroom temperature for two days. After the removal of solvent, the residuewas then dissolved in ethyl acetate and washed with saturated KHSO₄,saturated NaHCO₃, water and then dried over Na₂SO₄. The solvent wasevaporated, and the residue was flash chromatographed over silica gel(eluent: 1:5 v/v ethyl acetate-hexane) to give the product in 91% yield(14.3 g) as a yellow solid.

b)5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine.To a stirred solution of acetamidine hydrochloride (2.84 g, 30 mmol.) inDMF (20 mL) were added a solution of potassium tert-butoxide (2.46 g, 22mmol.) in DMP (20 mL) and a solution of the above yellow solid (6.32 g,20 mmol.) in DMF (20 mL) at 0° C. After the mixture was stirred for 15min at 0° C., p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol.) wasadded. The mixture was heated at 100-110° C. for 2 hrs. After cooling,it was quenched with 2N aqueous NaOH solution and extracted with ether.The organic layer was dried over Na₂SO₄ and evaporated. the residue wasflash chromatographed over silica gel (eluent: 100:5 v/v ethylacetate-2M ammonia in Methanol) to give the product in 42% yield (1.5 g)as an off-white solid.

c)5-Benzyloxycarbonyl-1-(5-bromopentyl)-6-(2,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine.To a suspension of NaH (123 mg, 60% dispersion in mineral oil, 3.08mmol.) in THF (5 mL) was added a solution of the above off-white solid(1.0 g, 2.8 mmol.) and HMPA (0.5 g, 2.8 mmol.) in THF (5 mL) at 0° C.After 15 min, 1,5-dibromopentane (1.53 mL, 11.2 mmol.) was added. Themixture was then refluxed for 30 min. The solid was filtered off. Afterthe removal of the solvent, the residue was flash chromatographed oversilica gel (eluent: ethyl acetate) to give the product in 78% yield (1.1g) as a yellow oil.

d)5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)pentyl)-2,4-dimethyl-pyrimidine.A mixture of the above yellow oil (1.62 g, 3.2 mmol.),4-methoxycarbonyl-4-phenyl piperidine (1.4 g, 6.4 mmol.), potassiumcarbonate (1.76 g, 12.7 mmol.), sodium iodide (0.45 g, 3.0 mmol.) and1,4-dioxane (15 mL) was refluxed overnight. The undissolved solid wasthen filtered off and the solvent was evaporated. The residue was flashchromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2Mammonia in methanol) to give the product in 66% yield (1.36 g) as ayellow oil.

e)5-Carboxy-6-(2,4-difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)pentyl)-2,4-dimethyl-pyrimidine.A solution of the above yellow oil (0.36 g, 0.56 mmol) in methanol (20mL) was subjected to hydrogenation with a H₂ balloon in the presence ofpalladium (36 mg, 5% on C). The reaction was carried out at roomtemperature for 30 min. The catalyst was then filtered off and thesolvent was removed in vacuo to give the product in quantitative yield(0.31 g) as an off-white solid.

f)6-(2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethyl-5-methylaminocarbonyl-pyrimidine.A mixture of the above off-white solid (0.244 g, 0.44 mmol.),4-dimethylaminopyridine (0.26 g, 2.12 mmol.),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g,0.66 mmol.) and CH₂Cl₂ (10 mL) was stirred at room temperature for 2hrs. After the addition of methyl amine hydrogen chloride (0.089 g, 1.32mmol.), the mixture was stirred at room temperature overnight. To themixture was added another 25 mL of CH₂Cl₂ and washed with saturatedNH₄Cl solution. After removal of the solvent, the residue was flashchramotographed over silica gel (eluent: 100:20 v/v ethyl acetate-2Mammonia in methanol) to give the title compound in 22% yield (0.055 g)as a yellow oil. Treatment of the free base with 2 equivalents of 1M HClin ether gave the HCl salt as a pale yellow solid: mp 152-155° C. Anal.Calcd. for C₃₂H₄₀F₂N₄O₃. 2HCl.1.6H₂O.0.8CHCl₃: C, 51.57; H, 6.07; N,7.33. Found: C, 51.38; H, 5.91; N, 7.27.

EXAMPLE 59

6(R,S)-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-4(S)-methyl)pentyl-2,4-dimethylpyrimidine

a) (S)-(+)-3-Methylpiperidine. A mixture of (+)-mandelic acid (45.64 g,0.3 mol) in ethyl acetate (300 mL) was heated to solution and treatedwith 3-methylpiperidine (29.75 g, 0.3 mol). The mixture was allowed tocome to room temperature before filtration. The crystalline material waswashed with 1:1 ethyl acetate-ether (400 mL). Two recrystallizations ofthis salt from ethyl acetate gave the optically pure salt in 56% yield(21.7 g).

b) (S)-(+)-N-Benzoyl-3-methylpiperidine. The above salt (21 g, 0.088mol) was dissolved in sodium hydroxide solution (1.0 N, 200 mL). Thesolution was cooled to 3° C., and benzoyl chloride (12.5 g, 0.089 mol)was added dropwise over 10 min. After the addition was complete, themixture was transferred to a separatory funnel and extracted with ether.The combined extracts were dried (Na₂SO₄) and concentrated to give thepure amide in 98% yield (17.2 g): [α]_(D)+45.9 (c=1.00, CH₃OH)

c) (S)-(−)-2-Methyl-1,5-dibromopentane. To the above amide powder wasadded phosphorus tribromide (7.81 mL, :d 2.85, 0.082 mol) at 5° C. over20 min with vigorous stirring. After the addition, the mixture waswarmed to room temperature, and Br₂ (4 mL, 0.082 mol) was added dropwiseover 10 min. The mixture was then allowed to stand at room temperatureovernight and distilled under vacuum (0.5-1 mm Hg) until the headtemperature reached 80° C. The distillate was dissolved in hexane (100mL) and washed successively with water (20 mL), concentrated sulfuricacid (4×30 mL), water (20 mL), NaOH solution (1N, 2×40 mL), and water(20 mL). The hexane solution was then dried (Na₂SO₄) and concentrated togive the product in 31% yield (6.4 g) as a light yellow liquid.

d)1-(5-Bromo-4(S)-methylpentyl)-6(R,S)-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.To a suspension of NaH (47 mg, 60% dispersion in mineral oil, 1.17mmol.) in THF (3 mL) was added a solution of6-(3,4-difluoro-phenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine(0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL) at 0°C. After 10 min, a solution of (−)-2-methyl-1,5-dibromopentane (0.86 g,3.53 mmol.) in THF (5 mL) was added. The mixture was then refluxed for10 min. The solid formed was filtered off. After the removal of thesolvent, the residue was flash chromatographed over silica gel (eluent:100:5 v/v ethyl acetate-2.0M ammonia in methanol) to give the product in36% yield (0.169 g) as a yellow oil.

e)6(R,S)-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl1--(5-(4-methoxycarbonyl-4—phenylpiperidin-1-yl)-4(S)-methyl)pentyl-2,4-dimethylpyrimidine.A mixture of the above yellow oil (0.169 g, 0.38 mmol.),4-methoxycarbonyl-4-phenyl piperidine (0.167 g, 0.76 mmol.), potassiumcarbonate (0.21 g, 1.52 mmol.), sodium iodide (0.057 g, 0.38 mmol.) and1,4-dioxane (8 mL) was refluxed overnight. The undissolved solid wasthen filtered off and the solvent was evaporated. The residue was flashchromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2Mammonia in methanol) to give the title compound in 11% yield (0.025 g)as a yellow oil. Treatment of the free base with 2 equivalents of 1M HClin ether gave the HCl salt as a light yellow solid: mp 155-158° C. Anal.Calcd. for C₃₃H₄₁F₂N₃O₄.2HCl.0.5H₂O: C, 59.72; H, 6.64; N, 6.33. Found:C, 59.47; H, 6.66; N, 6.10.

EXAMPLE 60

6-(3,4-Difuorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)methyl)benzyl-2,4-dimethylpyrimidine

a)1-(3-Bromomethylbenzyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.To a suspension of NaH (31 mg, 60% dispersion in mineral oil, 0.77mmol.) in THF (5 mL) was added a solution of6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine(0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (5 mL) at 0°C. After 15 min, α,α′-dibromo-m-xylene (0.99 g, 3.75 mmol.) was added.The mixture was then refluxed for 15 min. The solid was filtered off.After the removal of the solvent, the residue was flash chromatographedover silica gel (eluent: ethyl acetate) to give the product in 91% yield(0.45 g) as a yellow oil.

b)6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(3-(4-methoxycarbonyl-4-phenyl-4-phenylpiperidin-1-yl)methyl)benzyl-2,4-dimethylpyrimidine.

A mixture of the above yellow oil (0.45 g, 0.97 mmol.),4-methoxycarbonyl-4-phenyl piperidine (0.42 g, 1.9 mmol.), potassiumcarbonate (0.67 g, 4.86 mmol.), sodium iodide (0.14 g, 0.97 mmol.) and1,4-dioxane (10 mL) was refluxed overnight. The undissolved solid wasthen filtered off and the solvent was evaporated. The residue was flashchromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2Mammonia in methanol) to give the title compound in 17% yield (0.10 g) asa yellow oil. Treatment of the free base with 2 equivalents of 1M HCl inether gave the HCl salt as an off-white solid: mp 181-183° C. Anal.Calcd. for C₃₅H₃₇F₂N₃O₄.2HCl.1.0H₂O: C, 60.69; H, 5.97; N, 6.07. Found:C, 60.73; H, 5.77; N, 5.94.

EXAMPLE 61

6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(5-(3-phenylpropylamino)pentyl)-pyrimidine

A mixture of1-(5-bromopentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine(0.186 g, 0.433 mmol.), 3-phenyl-1-propylamine (0.12 g, 0.89 mmol.),potassium carbonate (0.3 g, 2.17 mmol.), sodium iodide (70 mg, 0.46mmol.) and 1,4-dioxane (8 mL) was refluxed overnight. The undissolvedsolid was then filtered off and the solvent was evaporated. The residuewas flash chromatographed over silica gel (eluent: 100:20:10 v/v/vCHCl₃-methanol-2M ammonia in methanol) to give the product in 54% yield(0.114 g) as a yellow oil. Treatment of the free base with 2 equivalentsof 1M HCl in ether gave the HCl salt as a white solid: mp 95-97° C.Anal. Calcd. for C₂₈H₃₅F₂N₃O₂.2HCl.0.5CH₂Cl₂: C, 57.15; H, 6.39; N,7.02. Found: C, 57.09; H, 6.65; N, 6.85.

EXAMPLE 62

(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-(2-pyridyl)piperidin-1-yl)pentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine

a) 3-Bromopropylepoxide.

To a solution of 5-bromo-1-pentene (2.15 g, 14.4 mmol.) in CH₂Cl₂ (40mL) was added MCPBA (3.0 g, 17.3 mmol.) at 0° C. slowly. After stirredat room temperature overnight, the mixture was poured into a mixture ofice and 2N NaOH solution. The separated aqueous layer was extracted withCH₂Cl₂. The combined organic layer was then washed with water, brine anddried over Na₂SO₄. The concentrated mixture was flash chromatographedover silica gel (eluent: CH₂Cl₂) to give the product in 92% yield (2.19g) as a pale yellow liquid.

b)1-(4,5-Epoxypentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.

To a suspension of NaH (78 mg, 60% dispersion in mineral oil) in THF (10mL) was added a solution of6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine(0.5 g, 1.78 mmol.) and HMPA (0.3 mL, 1.78 mmol.) in THF (5 mL) at 0° C.After 20 min, the above pale yellow liquid (0.6 g, 3.6 mmol.) was added.The mixture was then refluxed 2hrs. After the removal of the solvent,the residue was flash chromatographed over silica gel (eluent:100:5 v/vethyl acetate-2.0M ammonia in methanol) to give the product in 62% yield(0.4 g) as a yellow oil.

c)6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-(2-pyridyl)piperidin-1-)ylpentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine.

A mixture of the above yellow oil (0.48 g, 1.32 mmol.).4-(2-pyridyl)piperidine (0.32 g, 1.98 mmol.) and 1,4-dioxane (10 mL) wasrefluxed overnight. The concentrated mixture was then flashchromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2.0Mammonia in methanol) to give all four diastereomers in 43% yield (0.3g). Chiral HPLC separation gave the title enantiomer which was convertedto a HCl salt: [α]_(D)=120.6 (c=0.7, MeOH); mp 163-165° C. Anal. Calcd.for C₂₉H₃₆F₂N₄O₃.3HCl.0.7CHCl₃: C, 49.57; H, 5.56; N, 7.79. Found: C,49.41; H, 5.96; N, 7.38.

EXAMPLE 63

6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(5-(4-(2-pyridyl)piperidin-1-yl)-4-oxo)pentylpyrimidine

To a solution of oxalyl chloride (8 mg, 0.06 mmol.) in CH₂Cl₂ (0.25 mL)was added a solution of DMSO (10 mg, 0.14 mmol.) in CH₂Cl₂ (0.3 mL) at−78° C. After 3 min, a solution of6-(3,4-difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-(2-pyridyl)-piperidin-1-yl)pentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine(30 mg, 0.057 mmol.) in CH₂Cl₂ (1 mL) was added to the mixture which wasstirred for another 15 min. The mixture was treated with triethylamine(0.04 mL) and stirred for another 5 min. Then it was allowed to warm upto room temperature. After the addition of water, it was washed with 1NNaOH and water. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by preparative TLC (eluent:100:20 v/v ethyl acetate-2.0M ammonia in methanol) to give the titlecompound in 43% yield (13 mg) as a yellow oil. Treatment of the freebase with 3 equivalents of 1M HCl in ether gave the HCl salt as a paleyellow solid: mp 135-137° C. Anal. Calcd. for C₁₉H₃₄F₂N₄O₃.3HCl₂H₂O0.9CH₂Cl₂: C, 48.11; H, 5.78; N, 7.51. Found: C, 47.99; H, 6.08; N,7.35.

EXAMPLE 64

(+)-4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-1-yl)-pentyl-2(1H)-pyrimidone

a)3-(5-Bromopentyl)-4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-2(1H)-pyrimidone.

To a suspension of NaH (0.23 g, 60% dispersion in mineral oil, 5.8mmol.) in THF (40 mL) was added a solution of6-(3,4,5-trifluorophenyl-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-pyrimidine(0.6 g, 1.9 mmol.) and HMPA (0.33 mL, 1.9 mmol.) in THF (10 mL) at 0° C.After 20 min, 1,5-dibromopentane (1.75 g, 9.4 mmol.) was added. Themixture was then refluxed for 2 hrs and quenched by water. The mixturewas partitioned between ethyl acetate and water. The organic layer wasseparated, treated with 6N HCl (10 mL) solution and stirred at roomtemperature for 1 hr. It was then separated and dried over Na₂SO₄. Afterthe removal of solvent, the residue was flash chromatographed oversilica gel (eluent: 80:20 v/v hexane-ethyl acetate) to give the productin 73% yield (0.62 g) as a yellow oil.

b)(+)-4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-1-yl)-pentyl-2(1H)-pyrimidone. A mixture of3-(5-bromopentyl)-4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-2(1H)-pyrimidone(0.3 g, 0.7 mmol.), 4-(2-pyridyl) piperidine (0.22 g, 1.4 mmol.),potassium carbonate (0.5 g, 3.6 mmol.), sodium iodide (0.1 g, 0.7 mmol.)and acetone (20 mL) was refluxed overnight. The undissolved solid wasthen filtered off and the solvent was evaporated. The residue was flashchromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2.0Mammonia in Methanol) to give the racemic product in 85% yield (0.3 g) asa yellow oil. Chiral HPLC separation afforded the title enantiomer whichwas converted to a HCl salt: [α]_(D)=122 (c=4.1, MeOH); mp 125-127° C.Anal. Calcd. for C₂₈H₃₃F₃N₄O₃.2HCl.2H₂O.0.2Et₂O: C, 52.86; H, 6.32; N,8.56. Found: C, 52.66; H, 6.37; N, 8.15.

EXAMPLE 65

4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(3-(4-(2-pyridyl)piperidin-1-yl)propyloxycarbonyl)-2(1H)-pyrimidone.

a) 1-(3-Hydroxypropyl)-4-(2-pyridyl)piperidine.

A mixture of 4-(2-pyridyl)piperidine (200 mg, 1.23 mmol),3-bromopropanol (135 mL, 1.49 mmol), potassium carbonate (620 mg, 4.49mmol) and a catalytic amount of sodium iodide in acetone (10 mL) washeated at reflux overnight. Filtration followed by evaporation of thesolvent gave a light brown oil (324 mg) which was dissolved in CHCl₃ andflash chromatographed over silica gel (20 g) eluting withEtOAc/MeOH/Et₃N (20:1:1) to afford a light brown solid (166 mg, 61%).

b)

4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(3-(4-(2-pyridyl)piperidin-1-yl)propyloxycarbonyl)-2(1H)-pyrimidone.

A mixture of 1-(3-hydroxypropyl)-4-(2-pyridyl)-piperidine (72 mg, 0.33mmol) and4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(4-nitrophenoxycarbonyl)-2(1H)-pyrimidine(152 mg, 0.33 mmol) in dry THF (8 mL) was heated at reflux overnight.The residue obtained after evaporation of the solvent was dissolved inEtOAc and flash chromatographed over silica gel (18 g) eluting withEtOAc/MeOH/Et₃N (100:3:3) to afford an off-white solid (133 mg, 75%). Itwas dissolved in CH₂Cl₂ and treated with 1M HCl in ether (0.6 mL) togive an off-white solid: mp 154° C. (dec.). Anal. Calcd. forC₂₇H₂₉F₃N₄O₅.2HCl 2H₂O: C, 49.47; H, 5.38; N, 8.55. Found: C, 49.48; H,5.16; N, 8.35.

EXAMPLE 66

(+)-1,2,3,6-Tetrahydro-1-{N-[4-cyano-4-(phenyl)cyclohex-1-yl]ethyl}carboxamido-5-methoxy carbonyl-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.

a) 2-[4-Cyano-4-(phenyl)cyclohex-1-yl]ethylamine.

A mixture of 4-phenyl-4-cyanocyclohexanone (5.00 g, 25.09 mmol) andethylenediamine (5.58) and p-toluene sulfonic acid in benzene (200 mL)were refluxed for 4 h in a Dean-Stork set-up to remove the water formed.Solvent was evaporated and the residue was redissolved in methanol andcooled to 0° C. To this, sodium borohydride (1.5 g) was added inportions and the mixture was stirred at room temperature for 3 h.Solvent was evaporated, the residue was dissolved in dichloromethane(300 mL), washed with-brine (2×200 mL) and dried (sodium sulfate).Solvent was evaporated and the residue was dried under vacuum to leavethe product as an oil (5.2 g). The ¹H-NMR showed this product to be pureand found to contain the cis/trans isomers in the ratio of about 9:1. Itwas used as was in the next step.

b) (+)-1,2,3,6-Tetrahydro-1-{N-[4-cyano-4-(phenyl)cyclohex-1-yl]ethyl}carboxamido-5-methoxycarbonyl-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.

A solution of(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenoxy)carbonylpyrimidine(0.220 91 0.448 mmol),2-[4-cyano-4-(phenyl) cyclohex-1-yl]ethylamine(0.130 g, 0.538 mmol) in tetrahydrofuran (100 mL) was stirred at roomtemperature for 24 hours. The reaction mixture was stirred for another 1hour after addition of 2 mL of 6N HCl. Solvent was evaporated at reducedpressure and the residue was basified by treatment with 10% aqueous KOHsolution, extracted with dichloromethane (3×10 mL). The combinedextracts were dried over potassium carbonate, and solvent evaporated.The crude product was purified by preparative thin layer chromatography(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4). The two possibleisomer were obtained in the order of less polar compound as the minorproduct and the more polar compound as the major component (yields: 16mg minor and 160 mg major isomer). The HCl salts were obtained bytreatment with 1N HCl in ether. The minor isomer HCl salt:m.p. 124-126°C.; [α]_(D)=+112 (c=0.21 g in 100 mL CHCl₃); Anal. Calcd. forC₃₀H₃₄N₅O₅F₂Cl.0.5 chloroform. 0.5 ether: C, 54.61; H, 5.57; N, 9.80.Found: C, 54.43; H, 5.29; N, 9.54. The major isomer HCl salt: m. p.136-138° C.; [α]_(D)=+142 (c=0.21 g in 100 mL CHCl₃) Anal. Calcd. forC₃₀H₃₄N₅O₅F₂Cl.0.4 chloroform: C, 54.84; H, 5.21; N, 10.52. Found: C,55.16; H, 5.39; N, 10.42.

EXAMPLE 67

As a specific embodiment of an oral composition of a compound of thisinvention, 100 mg of one of the compounds described herein is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size O hard gel capsule.

Pharmacological Profiles of the Compounds in Cloned Human AdrenergicReceptors.

Binding affinities were measured for selected compounds of the inventionat six cloned human alpha-l and alpha-2 receptor subtypes, as well as atthe L-type calcium channel. The protocols for these experiments aregiven below.

Protocol for the Determination of the Potency of α₁ Antagonists

The activity of compounds at the different human receptors wasdetermined in vitro using cultured cell lines that selectively expressthe receptor of interest. These cell lines were prepared by transfectingthe cloned cDNA or cloned genomic DNA or constructs containing bothgenomic DNA and cDNA encoding the human α-adrenergic receptors asfollows:

α_(1A) Human Adrenergic Receptor: The entire coding region of α1A (1719bp), including 150 base pairs of 5′ untranslated sequence (5′ UT) and300 bp of 3′ untranslated sequence (3′ UT), was cloned into the BamHIand ClaI sites of the polylinker-modified eukaryotic expression vectorpCEXV-3, called EXJ.HR. The construct involved the ligation of partialoverlapping human lymphocyte genomic and hippocampal cDNA clones: 5′sequence were contained on a 1.2 kb SmaI-XhoI genomic fragment (thevector-derived BamHI site was used for subcloning instead of theinternal insert-derived SmaI site) and 3′ sequences were contained on an1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was from the vectorpolylinker). Stable cell lines were obtained by cotransfection with theplasmid α1A/EXJ (expression vector containing the α1A receptor gene) andthe plasmid pGCcos3neo (plasmid containing the aminoglycosidetransferase gene) into LM(tk-), CHO, and NIH3T3 cells, using calciumphosphate technique. The cells were grown, in a controlled environment(37° C., 5% CO₂), as monolayers in Dulbecco's modified Eagle's Medium(GIBCO, Grand Island, N.Y.) containing 25 mM glucose and supplementedwith 10% bovine calf serum, 100 units/ml penicillin g, and 100 μg/mlstreptomycin sulfate. Stable clones were then selected for resistance tothe antibiotic G-418 (1 mg/ml), and membranes were harvested and assayedfor their ability to bind [³H]prazosin as described below (see“Radioligand Binding assays”).

α_(1B) Human Adrenergic Receptor: The entire coding region of α1B (1563bp), including 200 base pairs and 5′ untranslated sequence (5′ UT) and600 bp of 3′ untranslated sequence (3′ UT), was cloned into the EcoRIsite of pCEXV-3 eukaryotic expression vector. The construct involvedligating the full-length containing EcoRI brainstem cDNA fragment from λZapII into the expression vector. Stable cell lines were selected asdescribed above.

α_(1C) Human Adrenergic Receptor: The entire coding region of α1C (1401bp), including 400 base pairs of 5′ untranslated sequence (5′ UT) and200 bp of 3′ untranslated sequence (3′ UT), was cloned into the KpnIsite of the polylinker-modified pCEXV-3-derived eukaryotic expressionvector, EXJ.RH. The construct involved ligating three partialoverlapping fragments: a 5′ 0.6 kb HincII genomic clone, a central 1.8EcoRI hippocampal cDNA clone, and a 3′ 0.6 Kb PstI genomic clone. Thehippocampal cDNA fragment overlaps with the 5′ and 3′ genomic clones sothat the HincII and PstI sites at the 5′ and 3′ ends of the cDNA clone,respectively, were utilized for ligation. This full-length clone wascloned into the KpnI site of the expression vector, using the 5′ and 3′KpnI sites of the fragment, derived from vector (i.e., pBluescript) and3′-untranslated sequences, respectively. Stable cell lines were selectedas described above.

Radioligand Binding Assays: Transfected cells from culture flasks werescraped into 5 ml of 5 mM Tris-HCl, 5 mM EDTA, pH 7.5, and lysed bysonication. The cell lysates were centrifuged at 1000 rpm for 5 min at4° C., and the supernatant was centrifuged at 30,000× g for 20 min at 4°C. The pellet was suspended in 50 mM Tris-HCl, 1 mM MgCl₂, and 0.1%ascorbic acid at pH 7.5. Binding of the α1 antagonist [³H]prazosin (0.5nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-)cells was done in a final volume of 0.25 ml and incubated at 37° C. for20 min. Nonspecific binding was determined in the presence of 10 μMphentolamine. The reaction was stopped by filtration through GF/Bfilters using a cell harvester. Inhibition experiments, routinelyconsisting of 7 concentrations of the tested compounds, were analyzedusing a non-linear regression curve-fitting computer program to obtainKi values.

α₂ Human Adrenergic Receptors: To determine the potency of c antagonistsat the α₂ receptors, LM(tk-) cell lines stably transfected with thegenes encoding the α_(2A), α_(2B), and α_(2C) C receptors were used. Thecell line expressing the α_(2A) receptor is designated L-α_(2A), and wasdeposited on Nov. 6, 1992 under ATCC Accession No. CRL 11180. The cellline expressing the α_(2B) receptor is designated L-NGC-α_(2B), and wasdeposited on October 25, 1989 under ATCC Accession No. CRL10275. Thecell line expressing the α_(2C) receptor is designated L-α_(2C), and wasdeposited on Nov. 6, 1992 under ATCC Accession No. CRL-11181. Celllysates were prepared as described above (see Radioligand BindingAssays), and suspended in 25 mM glycylglycine buffer (pH 7.6 at roomtemperature). Equilibrium competition binding assay were performed using[3H]rauwolscine (0.5 nM), and nonspecific binding was determined byincubation with 10 μM phentolamine. The bound radioligand was separatedby filtration through GF/B filters using a cell harvester.

Determination of the Activity of α₁ Antagonists at Calcium Channels

The potency of α₁ antagonists at calcium channels was determined incompetition binding assays of [3H]nitrendipine to membrane fragments ofrat cardiac muscle, essentially as described by Glossman and Ferry(Methods in Enzymology 109:513-550, 1985). Briefly, the tissue wasminced and homogenized in 50 mM Tris-HCl (pH 7.4) containing 0.1 mMphenylmethylsulfonyl fluoride. The homogenates were centrifuged at 1000g for 15 minutes, the resulting supernatant was centrifuged at 45,000 gfor 15 minutes. The 45,000 g pellet was suspended in buffer andcentrifuged a second time. Aliquots of membrane protein were incubatedfor 30 minutes at 37° C. in the presence of [3H]nitrendipine (1 nM), andnonspecific binding was determined in the presence of 10 μM nifedipine.The bound radioligand was separated by filtration through GF/B filtersusing a cell harvester.

The compounds described above were assayed using cloned human alphaadrenergic receptors and the rat calcium channel. The preferredcompounds were found to be selective α_(1C) antagonists. The bindingaffinities of compounds 19-23 are illustrated in the following table.Binding affinities of compounds 19-23 at cloned human α1a, α1b and α1creceptors.

hα1a hα1b hα1c Example pKi SEM n pKi SEM n pKi SEM n 19 6.14 0.02 3 6.210.09 3 9.74 0.02 3 20 6.46 0.04 3 6.59 0.08 3 9.68 0.05 3 21 6.01 0.03 36.33 0.06 3 9.41 0.09 3 22 6.24 0.06 3 6.37 0.06 3 9.54 0.09 3 23 6.170.04 4 6.32 0.06 4 8.99 0.12 4 h = human

What is claimed is:
 1. A compound having the structure:

wherein A is

wherein each of Y₁, Y₂, Y₃, Y₄ and Y₅ is independently —H; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; —F, —Cl,—Br, or —I; —NO₂; —N₃; —CN; —OR₃, —OCOR₃, —COR₃, —CONHR₃, —CON(R₃)₂, or—COOR₃; or any two of Y₁, Y₂, Y₃, Y₄ and Y₅ present on adjacent carbonatoms can constitute a methylenedioxy group; wherein X is S; O; or NR₃;wherein R₁ is —H; —NO₂; —CN; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; —N(R₃)₂; —OR₃; —(CH₂)_(p)OR₃;—COR₃; —CO₂R₃; or —CON (R₃)₂; wherein R₂ is —H; straight chained orbranched C₁-C₇ alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,monofluoroalkyl or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; C₃-C₁₀ cycloalkyl-C₁-C₁₀-alkyl,C₃-C₁₀ cycloalkyl-C₁-C₁₀-monofluoroalkyl or C₃-C₁₀cycloalkyl-C₁-C₁₀-polyfluoroalkyl; —CN; —CH₂XR₃, —CH₂X(CH₂)_(p)NHR₃,—(CH₂)_(n)NHR₃, —CH₂X(CH₂)_(p)N(R₃)₂, —CH₂X(CH₂)_(p)N₃, or—CH₂X(CH₂)_(p)NHCXR₇; or —OR₃; wherein each p is independently aninteger from 1 to 7; wherein each n is independently an integer from 0to 5; wherein each R₃ is independently —H; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; or C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R₄is

wherein R₄ in the immediately preceding structure is —H; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl; or C₃-C₇cycloakyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl,

wherein Z is C₂-C₇ alkenylene or alkynylene; CH₂; O; CONR₃; S; SO;SO_(2 ;) or NR₃; wherein each D is independently CH₂; O; S; NR₃; CO; orCS; wherein W is C═O; C═NOR₃; or substituted or unsubstituted phenyl,pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl,imidazolyl, benzofurazanyl, benzofuranyl or benzimidazolyl, wherein thephenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl,indolyl, imidazolyl, benzofurazanyl, benzofuranyl or benzimidazolyl issubstituted with —H, —F, —Cl, —Br, —I, —NO₂, —CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₁-C₇monofluoroalkyl, straight chained or branched C₁-C₇ polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl, straight chained or branchedC₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ monofluorocycloalkyl, C₃-C₇polyfluorocycloalkyl, C₃-C₇ cycloalkenyl, —N(R₃)₂, —OR₃, —COR₃, —CO₂R₃,or —CON(R₃)₂; wherein each V is independently O; S; CR₅R₇; C(R₇)₂; orNR₇; wherein each m is independently an integer from 0 to 3; wherein ois an integer from 1 to 3; wherein each R is independently —H; —F;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;—N(R₃)₂; —NO₂; —CN; —CO₂R₃; or —OR₃; wherein R₅ is —H; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; phenyl,thiophenyl, pyridyl, pyrrolyl, furanyl, imidazolyl or indolyl; or—COOR₃, —COR₃, —CONHR₃, —CN, or —OR₃; wherein each R₆ is independently—H; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or —OR_(3;)wherein each R₇ is independently —H; substituted or unsubstitutedbenzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl,pyrrolyl, naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl,benzimidazolyl or 2-keto-1-benzimidazolinyl, wherein the benzyl,benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrrolyl,naphthyl, indolyl, imidazolyl, benzofurazanyl, benzofuranyl,benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with —H, —F,—Cl, —Br, —I, —NO₂, —CN, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₁-C₇ monofluoroalkyl, straight chained orbranched C₁-C₇ polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl, straight chained or branched C₂-C₇ alkynyl, C₃-C₇ cycloalkyl,C₃-C₇ monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₃-C₇cycloalkenyl, —N(R₃)₂, —OR₃, —COR₃, —CO₂R₃, or —CON(R₃)₂; substituted orunsubstituted straight chained or branched C₁-C₇ alkyl, monofluoroalkylor polyfluoroalkyl; substituted or unsubstituted straight chained orbranched C₂-C₇ alkenyl or alkynyl; or C₃-C₇ cycloalkyl or cycloalkenyl,wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl is substituted with —H, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzofurazanyl, benzofuranyl, or benzimidazolyl; and wherein R₈ is —H;substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzofurazanyl, benzofuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzofurazanyl, benzofuranyl, benzimidazolyl or2-keto-1-benzimidazolinyl is substituted with —H, —F, —Cl, —Br, —I,—NO₂, —CN, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₁-C₇ monofluoroalkyl, straight chained or branched C₁-C₇polyfluoroalkyl, straight chained or branched C₂-C₇ alkenyl, straightchained or branched C₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₃-C₇ cycloalkenyl,—N(R₃)₂, —OR₃, —COR₃, —CO₂R₃, or —CON(R₃)₂; substituted or unsubstitutedstraight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; substituted or unsubstituted straight chained orbranched C₂-C₇ alkenyl or alkynyl; or C₃-C₇ cycloalkyl or cycloalkenyl,wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl is substituted with —H, phenyl, pyridyl,thiophenyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl,benzofurazanyl, benzofuranyl, benzimidazolyl, —N(R₃)₂, —NO₂, —CN,—CO₂R₃, —OR₃;

or a pharmaceutically acceptable salt thereof.
 2. An enantiomer of thecompound of claim
 1. 3. An (−) enantiomer of the compound of claim
 1. 4.The compound of claim 1 having the structure:


5. The compound of claim 1 having the structure:


6. The compound of claim 5, having the structure:

wherein V is selected from CR₅R₇ or NR, and p is selected from 1-3. 7.The compound of claim 6, wherein the compound is selected from the groupconsisting of:


8. A compound according to claim 1, wherein the compound is:


9. A compound according to claim 1, wherein the compound is(+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.10. A compound according to claim 1, wherein the compound is6-(3,4-Difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxypyrimidine-5-carboxylicacid.
 11. A pharmaceutical composition comprising an amount of thecompound of claim 1, 8, 9 or 10 effective to treat benign prostatichyperplasia and a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition comprising an amount of the compound of claim1, 8, 9 or 10 effective to relax lower urinary tract tissue and apharmaceutically acceptable carrier.
 13. A pharmaceutical compositioncomprising an amount of the compound of claim 1, 8, 9 or 10 effective totreat benign prostatic hyperplasia, an amount of finasteride effectiveto treat benign prostatic hyperplasia and a pharmaceutically acceptablecarrier.
 14. A pharmaceutical composition comprising an amount of thecompound of claim 1, 8, 9 or 10 effective to relax lower urinary tracttissue, an amount of finasteride effective to relax lower urinary tracttissue and a pharmaceutically acceptable carrier.
 15. A method oftreating a subject suffereing from benign prostatic hyperplasia whichcomprises administering to the subject an amount of the compound ofclaim 1, 7, 8, 9 or 10 effective to treat benign prostatic hyperplasia.16. A method of treating a subject suffering from benign prostatichyperplasia which comprises administering to the subject an amount ofthe compound of claim 1, 8, 9, or 10 in combination with a 5alpha-reductase inhibitor effective to treat benign prostatichyperplasia.
 17. The method of claim 16 wherein the 5-alpha reductaseinhibitor is finasteride.
 18. A method relaxing lower urinary tracttissue which comprises contacting the lower urinary tract tissue with anamount of the compound of claim 1, 8, 9 or 10 effective to relax lowerurinary tract tissue.
 19. The method of claim 18, wherein the lowerurinary tract tissue is urethral smooth muscle.
 20. A method of relaxinglower urinary tract tissue in a subject which comprises administering tothe subject an amount of the compound of claim 1, 8, 9 or 10 effectiveto relax lower urinary tract tissue.
 21. The method of claim 20, whereinlower urinary tract tissue is urethral smooth muscle.